
Gass. 
Book 









SEMICENTENNIAL PUBLICATIONS 

OF THE 

UNIVERSITY OF CALIFORNIA 




1868-1918 



TYPHOID FEVER 

CONSIDERED AS A PROBLEM OF SCIENTIFIC 
MEDICINE 



THE MACMILLAN COMPANY 



MACMILLAN & CO., Limited 



MACMILLAN CO. OF CANADA, Ltd. 

TORONTO 



TYPHOID FEVER 



CONSIDERED AS A PROBLEM jOF SCIENTIFIC 
MEDICINE 



BY 



*y 



FREDERICK Pf GAY 

M 
PROFESSOR OP PATHOLOGY IN THE UNIVERSITY OP CALIFORNIA 



Sfom fork 

THE MACMILLAN COMPANY 

1918 

All rights reserved 



>y 



Copyright, ;.1918 

Bt THE MACMILLAN COMPANY 

Set up and printed. Published, January, 1918 



07 of J. 

SEP 25 »92Q 



PREFACE 

This treatise is an attempted exposition of the problem of 
typhoid fever. It aims to treat historically the development and 
present status of our knowledge concerning this important malady 
as viewed from the standpoint of its mechanism. It is not pri- 
marily designed to aid directly in the clinic or the laboratory, but 
should serve to point out the relations of one to the other, to indi- 
cate the dependence of practice on theory, and the happy appli- 
cability to human need of investigation that may have seemed to 
aim merely at the gratification of intellectual curiosity. 

There are numerous admirable clinical treatises on typhoid 
fever, such as those of Curschmann, of Vincent and Muratet and of 
McCrae. The purely laboratory and the public health aspects of 
the disease are well summarized in such works as those of Kutscher, 
of Chapin and of Whipple. This book aims to strike a balance 
between these sources of information, following the life history of 
the typhoid bacillus rather than the manifestations of the disease it 
produces, in order to gain insight into the nature of the problem 
as a whole. 

No attempt has been made to make this work encyclopedic in 
character, although the references to original sources are suffi- 
ciently ample to lead a prospective investigator to full sources of 
information. Although we may have succeeded in maintaining 
correct proportions in our estimate of the accuracy and value of 
facts, methods and theories that have been shaken down by time 
into their proper relations to one another, we shall unconsciously 
or wilfully have exaggerated the importance of recent contribu- 
tions. We may well have overemphasized the importance of 
modern investigations in respect to antityphoid vaccination and 
specific therapy in typhoid fever through personal enthusiasm. 
The data on these aspects of typhoid fever are so ample and so 
recent that a critical summary of their essentials seems desirable, 
even though somewhat premature. 

In addition to the use that has been made of all the general 
treatises and original sources of information to be cited, particular 
indebtedness is felt to Charles Murchison's "Treatise on the 
Continued Fevers" as furnishing the backbone of the discus- 
sion of the earlier historical aspects of typhoid fever. The author 
wishes to express his thanks to Dr. John N. Force, Miss Ruth 
Stone and Miss Helen Dunbar for suggestions and aid in preparing 
the manuscript. 



TABLE OF CONTENTS 

CHAPTER I 

A GENERAL SURVEY OF THE DEVELOPMENT OP KNOWLEDGE CONCERNING TTPHOn> 

FEVER 

PAGE 

Progress in the Differential Diagnosis of Typhoid on the Basis of Symp- 
tomatology and Morbid Anatomy 1 

Development of the Conception of Contagion in Typhoid Fever 6 

The Advent of Bacteriology and Its Importance in the Explanation and 
Prevention of Typhoid Fever 8 

CHAPTER II 

TYPHOm FEVER AS A CAUSE OF DEATH AND DISABILITY 

The Significance of Typhoid Fever in Mortality Statistics 13 

Chronological Changes in the Typhoid Death Rate 15 

Typhoid Fever in Armies 21 

The Present Economic Loss from Typhoid 22 

CHAPTER III 

THE TYPHOH) BACILLUS 

Bacillus Typhosus as the Cause of Typhoid Fever 25 

The Cultural Characteristics of Bacillus Typhosus 25 

Biological Peculiarities Which Serve to Differentiate the Typhoid Bacillus 

from Other Bacteria 28 

The Toxins of Bacillus Typhosus 31 

Mutations and Variations in Bacillus Typhosus 34 

CHAPTER IV 

THE MODES OF INFECTION IN TYPHOH) FEVER 

Transmissibility of Typhoid Fever and General Conceptions of Its Modes 

of Infection 39 

Sources of Infection from the Typhoid Patient 42 

The Typhoid Bacillus at Large 45 

Routes Followed by the Typhoid Bacillus from one Individual to Another 46 

Contact Infections in Typhoid 46 

Direct Contact 46 

Indirect Contact and Its Several Channels to the Individual 47 

Water Infections in Typhoid and Its Several Routes in Reaching the 

Individual 50 

Relative Importance of Various Routes of Infection 56 



riii CONTENTS 

PAGE 

General Factors Which Influence the Occurrence of Typhoid Fever 56 

Extrinsic Factors 56 

Intrinsic Factors 58 

CHAPTER V 

THE PATHOGENESIS OP TYPHOID PEVEB 

General Symptomatology of Typhoid Fever 61 

The Incubation Period 63 

The Portal of Entry 66 

Localization of the Typhoid Bacillus in the Body During the Course of 

the Disease 70 

The Cause of the Fever in Typhoid 72 

Metastatic Foci of Typhoid Bacilli 73 

The Bone Marrow in Typhoid 74 

The Gall Bladder in Typhoid Fever 75 

The Toxins of the Typhoid Bacillus in Their Relation to the Disease 

Process 77 

The Complications in Typhoid 78 

Complications in General and Causes of Death 78 

Hemorrhage and Perforation 79 

Relapses 81 

Experimental Typhoid Fever in Animals 83 

CHAPTER VI 

THE DIAGNOSIS OP TYPHODD FEVEH 

Clinical Diagnosis and Its Limitations 87 

Laboratory Diagnosis of Typhoid Fever 88 

Detection of the Typhoid Bacillus in the Body 88 

Isolation of the Bacillus from the Blood 89 

Isolation of the Bacillus from the Stools 94 

Isolation of the Bacillus from the Bile 97 

Isolation of Typhoid Bacilli from the Urine 98 

The Differential Diagnosis of Bacillus Typhosus 98 

Diagnosis of Typhoid Fever Based on Specific Reactions on the 

Part of the Patient 100 

Serum Reactions 100 

Agglutination 101 

Fixation Reactions in Typhoid 105 

The Bactericidal Property of the Serum of Typhoid Patients. . 106 

Tropins or Opsonins in Typhoid Serum 106 

Methods of Diagnosis Depending on Evidence of Localized Hyper- 
susceptibility in the Patient 107 

Diagnostic Reactions Dependent on Changed Metabolism in Ty- 
phoid Fever 107 






CONTENTS ix 

PAGE 

Changes in the Leucocyte Count in the Course of Typhoid Fever. . . 108 
Summary of the Diagnostic Value of the Various Laboratory Tests. . 109 

CHAPTER VII 

THE SEQUELS OF TYPHOID FEVER AND THE CARRIER CONDITION 

Sequels After Bacteriological Cure Ill 

Typhoid Sequelae Due to Persistence of the Typhoid Bacillus in the Body 113 

Localized Pyogenic Foci 113 

Gall Bladder Infection 114 

Jaundice and Cholecystitis 116 

Gall Stones 117 

The Carrier State 119 

Classification of Typhoid Carriers 120 

Urinary Carriers 120 

Carriers in Recovered Typhoid Cases 121 

Convalescent 121 

Chronic 122 

Precocious or Incubation Period Carriers 123 

Healthy Carriers 124 

Importance of Carriers as a Source of Typhoid Fever 126 

General Facts in Reference to Carriers 128 

The Detection of Carriers 129 

CHAPTER VIII 

GENERAL MEASURES OF PREVENTION OF TYPHOID FEVER 

The Prevention of Typhoid Fever at Its Source 131 

Prevention of the Extension of Typhoid Fever from Typhoid Patients . . 132 

Prevention of Extension from Typhoid Carriers 135 

The Detection of Carriers 136 

General Methods of Dealing with Recognized Carriers 136 

Treatment of the Carrier State 138 

The Suppression of Typhoid Infection in Its Transit from one Individual 

to Another 141 

Measures of Protecting Possible Victims of Typhoid Infection 142 

CHAPTER IX 

NATURAL AND ACQUIRED RESISTANCE TO TYPHOID FEVER 

Evidence for Natural, Individual and Racial Immunity from Typhoid. . 145 

Immunity from Typhoid Acquired by Recovery from the Disease 147 

Recurrence of Typhoid Fever 147 

The Nature of Protection Afforded by Recovery from Typhoid. . . . 149 

The Typhoidin Test in Typhoid Recoveries 151 



x CONTENTS 

CHAPTER X 

ARTIFICIAL IMMUNIZATION AGAINST TYPHOID FEVER 

PAGE 

Historical Aspects of Typhoid Immunization 155 

Preparations of the Typhoid Bacillus That Have Been Used as Vaccines 156 

Killed Cultures of the Typhoid Bacillus 156 

Bacterial Extracts 158 

Living Cultures of the Typhoid Bacillus 159 

Sensitized Cultures of the Typhoid Bacillus 159 

Methods of Administration of Typhoid Vaccine 164 

The Immediate Effects Following Antityphoid Inoculation 166 

CHAPTER XI 

THE PROTECTIVE VALUE OF VACCINATION AGAINST TYPHOID FEVER 

Statistical Value of Results of Vaccination Available 172 

Vaccination in Armies 173 

Results in the English Army 174 

Results in the French Army 177 

Results in the French Navy 178 

Results in the Russian Army 178 

Results in the Italian Army 179 

Results in the Japanese Army and Navy 179 

Results in the German Army 180 

Results in the United States Army 181 

Results in the United States Navy 182 

Antityphoid Vaccination in Institutions 184 

Vaccination Among Physicians and Nurses 184 

Vaccination Among Laboratory Workers 185 

Results of Typhoid Vaccination in Civil Communities 185 

Typhoid Fever in the Vaccinated 186 

Paratyphoid Fever in Typhoid Vaccinated Individuals 189 

Multiple Vaccination 191 

Duration of the Protection Afforded by Antityphoid Vaccination 192 

CHAPTER XII 

THE PARATYPHOIDAL INFECTIONS 

Diseases in Man and Animals Produced by Bacteria of the Paratyphoid 

Group 198 

Clinical Differential Diagnosis of Paratyphoid Fever 202 

The Laboratory Diagnosis of Paratyphoid Fever 204 

Blood Cultures in Paratyphoid Cases 205 

Diagnosis of Paratyphoid Infections by means of Agglutination Tests. . 208 

The Incidence of Paratyphoid Fever 209 

Epidemiology in Paratyphoid Infections 211 

Prophylaxis in Paratyphoid Infections 212 



CONTENTS xi 

CHAPTER XIII 

THE TREATMENT OP TYPHOID FEVER 

PAGE 

The Influence of Diet in Typhoid Fever 214 

Hydrotherapy in Typhoid Fever 215 

Treatment of Typhoid Fever by Means of Sera 217 

Use of Serum of Recovered Cases 217 

Autoserumtherapy 217 

Specific Immune Sera 217 

Antiserum of Chantemesse 219 

Besredka's Antiserum 219 

Rodet's Antiserum 220 

Vaccine Treatment in Typhoid 221 

Comparative Results with Various Vaccines and Different Modes 

of Administration 221 

Intravenous Vaccine Therapy 222 

Non-Specificity of Vaccine Therapy in Typhoid 235 

The Mechanism of Cure in Intravenous Vaccine Therapy 236 

CHAPTER XIV 

SUGGESTED METHODS OF ADVANCE IN SOLVING THE TYPHODD PROBLEM 240 

BIBLIOGRAPHICAL INDEX OF REFERENCES QUOTED 245 






TYPHOID FEVER 

CONSIDERED AS A PROBLEM OF SCIENTIFIC 
MEDICINE 



TYPHOID FEVER CONSIDERED AS A PROBLEM 
OF SCIENTIFIC MEDICINE 

CHAPTER I 

A~ r GENERAL SURVEY OF THE DEVELOPMENT OF 
~ KNOWLEDGE CONCERNING TYPHOID FEVER 

Progress in medicine depends on the gradual recognition and 
separation of disease entities. Differential diagnosis must precede 
all rational means of prevention and therapy, and in each of these 
phases of progress the older methods of bedside observation and 
experience have been increasingly supplemented by methods of 
laboratory precision. No disease illustrates better the successive 
stages of scientific medical advance than typhoid fever, which 
as a cause of death and economic loss has been one of the world's 
greatest scourges. A survey of the useful knowledge that we have 
gained in respect to this disease is at once of historic interest, as 
bearing on medical progress, and of promise to those who trust 
in "Man's redemption of man." 

PROGRESS IN THE DIFFERENTIAL DIAGNOSIS OF TYPHOID ON THE 
BASIS OF SYMPTOMATOLOGY AND MORBID ANATOMY 

The disease we now recognize as typhoid or enteric fever is one 
of those continued fevers which was for centuries confused with 
other lasting fevers of somewhat similar appearance. Even today 
mistaken diagnoses are frequent, unless the most modern methods 
of laboratory aid are resorted to. Among those fevers which may 
be confused with typhoid may be mentioned recurrent fever, septic 
infection, malaria, tuberculosis, trichiniasis, and, particularly, 
typhus fever. The recognition of a disease entity like typhoid 
is, of course, more readily made in face of an epidemic than in an 
individual case. In the gradual differential recognition of typhoid 
fever we find certain characteristics which have been evident from 
the first. One of the most striking things about typhoid fever 
is its seasonal occurrence, and we find that Hippocrates, in the 
course of two successive autumns, met with many cases of a fever 

1 



2 TYPHOID FEVER 

of the continuous type, characterized by diarrhea, offensive watery 
stools, bilious vomiting, tympanites, abdominal pain, red rashes, 
epistaxis, sleeplessness, and in some cases a tendency to coma, 
delirium and subsultus, irregular remissions, and a lengthened 
duration, accompanied by increasing emaciation. Galen classified 
under the larger grouping of Hemitritceus a variety of bilious fever 
which may also have been typhoid. 

We may continue our historical survey by dividing the criteria 
of differentiation into two rather arbitrary groups. First of all, 
may be cited those criteria which are based on purely clinical, 
observational grounds, and on the basis of experience, and, 
secondly, those criteria which depend on the recognition of def- 
inite changes in anatomic structure. It is obvious that chrono- 
logically these two groups of observations will overlap to a 
considerable extent, but the separation may serve to show the 
limitation of each type of investigative procedure. 

Following the observations of Hippocrates and Galen, which 
have been mentioned, Spigelius in 1624 noted the occurrence of a 
fever characterized by the presence of abdominal pain, diarrhea, 
with sometimes melena, absence of crisis, and occasional relapses. 
In 1659 Thomas Willis * of England was first to make an attempt 
at separation of typhoid fever from typhus or febris pestilens, with 
which it was still destined for many years to remain confused. 
He made his differentiation on the basis of the fact that typhoid 
fever is less contagious, has little or no eruption, an imperfect 
crisis, and is prone to local complication. In 1734 Ebenezer 
Gilchrist described typhoid fever under the name of "nervous 
fever," which he characterized by its long duration, the occurrence 
of diarrhea, abdominal pain, blood in the stools, epistaxis, and 
"partial sweats which gave no relief." A further and more com- 
plete separation between typhus and typhoid fever was made by 
Langrish in the following year, who separated the two diseases 
under the headings of "slow, nervous fever," and "malignant, 
continued fever." A further amplification of this separation was 
made by Huxham (1739), who described the two fevers as "slow, 
nervous fever," on the one hand, and "putrid, malignant, petechial 
fever," on the other. About the year 1850 a discussion arose be- 
tween Sir John Pringle and Professor De Haen of Vienna, in ref- 
erence to the advisability of bloodletting in fevers. This discus- 
sion is now of no particular interest as bearing on treatment, but 
served to bring forward a point in differential diagnosis between 
the eruptions of typhus and of typhoid. It appears that Pringle 
was describing bloodletting in typhus fever, whereas the cases 



GENERAL SURVEY 3 

which De Haen had treated were typhoid. It remained for 
Pringle to recognize the fact that they had been describing two 
different forms of disease, and he makes the statement that the 
miliary fever or typhoid of De Haen occurs in all ranks of people 
and is characterized by a petechial and miliary eruption, whereas 
the fever which he had been studying, the malignant fever, occurs 
only among people who are crowded together in such close and 
foul places as military hospitals, jails, and transport ships. In 
1772 Dr. Macbride of Dublin spoke of "febris nervosa," a pro- 
tracted fever attended by diarrhea, as different from the putrid, 
continual fever which was contagious and accompanied by a florid 
eruption which gradually passed into petechise. 

We may now turn to the differentiation of typhoid fever on the 
basis of changes in anatomic structure, at once a surer and more 
scientific basis of classification. It appears that the lesions of 
typhoid fever were first referred to by Spigelius in 1624, who called 
attention to an inflammation and sometimes gangrene and sphace- 
lus of both large and small intestines. In 1682 Willis 2 made 
these observations much more definite by describing, in the less 
contagious of the two diseases which he attempted to differentiate, 
pustules like those of variola and ulcers in the small intestines, 
accompanied by swelling of the mesenteric nodes. In 1696 Baglivi 
called this fever "febris mesenterica" on account of the enlarge- 
ment of the mesenteric glands which he found associated with the 
intestinal inflammation. He also separated the disease from 
typhus or febris pestilens. Hoffmann in 1699 described gangrene 
and sloughing of the small intestine as associated with typhoid. 
Lancisi in 1718 first described typhoid perforation, which, how- 
ever, he incorrectly attributed to the presence of certain lum- 
bricoid worms in the intestines. In a form of fever which he refers 
to as Lent or symptomatic fever, Strother in 1729 described in- 
flammation and an "ulcer fixed on some of the bowels." The 
characteristic lesions of typhoid were more definitely localized by 
Riedel in 1748, who described "febris intestinalis," accompanied 
by gangrene of the lower ileum. A definite and full description of 
the characteristic intestinal lesions of typhoid fever is usually 
attributed to two German investigators, Roederer and Wagler 
(1762). After a careful inspection of the original treatise, we 
agree with Murchison, however, that it is practically certain that 
these investigators were not dealing with typhoid at all. In their 
thirteen cases, the post-mortem appearances of which are de- 
scribed with great minuteness, we find no description of ulceration 
of the ileum, whereas the lesions described are almost entirely 



4 TYPHOID FEVER 

confined to the stomach or to the large intestines. It is probable, 
then, that the German investigators were in reality dealing with 
an epidemic of typhus, complicated by dysentery, as Murchison 
has suggested. It appears that the intestinal lesions of typhoid 
did not escape the keen observation of John Hunter, as is shown by 
two preparations in his museum at the Royal College of Surgeons, 
one of which was later figured in a publication by Matthew 
Baillie. 

It remained, however, for a group of French investigators in 
the early part of the nineteenth century to describe with fullness 
and accuracy the lesions which we now recognize as being char- 
acteristic of typhoid. In 1804 Prost described ulcerations in the 
mucosa of the intestines and also a mild type of inflammation, 
which, however, was in all probability a simple post-mortem 
change. In 1813 Petit and Serres described in their "Fievre 
entero-mesenterique" lesions which were limited to the lower 
ileum and were specific, differing in many particulars from the 
ordinary type of inflammation which occurs in simple enteritis. 
They believed, moreover, that these lesions preceded and were 
the cause of this fever. In 1826 Bretonneau described typhoid 
under the name of "dothienenteritis," which he found charac- 
terized by lesions localized in the agminated and solitary glands 
of the ileum. He thought, moreover, that this disease was due to a 
poison, transmissible from the sick to healthy individuals, which 
suggestion may be regarded as the first definite contribution to 
the means of transmission in typhoid fever. Bretonneau further 
made the important observation that there is no definite relation 
between the severity of the disease and lesions produced. These 
observations were confirmed and amplified in the same year and 
independently by Hewitt of London, who also described the 
lesions of the solitary and agminated follicles. The further ob- 
servations of Louis in 1829 and of Chomel (1834) served still 
further to separate typhoid from simple gastro-enteritis, and also 
to point out the lesions of the lymph follicles. 

We find, then, at the beginning of the nineteenth century that a 
pretty clear picture of typhoid fever had been developed, at first on 
clinical grounds, and later on the basis of post-mortem appearance. 
There remained, however, for several years confusion between the 
two diseases, typhus and typhoid, owing largely to the fact that 
few observers had been able to compare them at first hand. We 
have mentioned the criteria of differentiation on a purely clinical 
basis by Willis and Huxham, and other similar observations were 
also made by Hildenbrand in Germany in 1810, who separated 



GENERAL SURVEY 5 

"contagious typhus" from "non-contagious, nervous fever," a 
separation which was further amplified by the work of Schoenlein 
in 1839, who gave names to the two diseases, which still unfor- 
tunately persist in Germany, namely, "typhus exanthematicus" 
and "typhus abdominalis." The objection to these terms lies not 
in their original form but in the abbreviation of "typhus," which 
is frequently used indiscriminately for typhus and typhoid. 

The valuable anatomic work of Bretonneau, Louis, and Chomel 
was not immediately of great service in the separation of typhus 
from typhoid, owing to the fact that the French investigators had 
no opportunity of studying typhus fever, a disease which in their 
time prevailed primarily in England. They were, indeed, inclined 
to regard typhus in England as identical with the French typhoid 
fever, and they regret that no careful anatomical observations were 
made by the English observers. Dr. H. P. Lombard of Geneva in 
1836, on the basis of study of fever both in France and England, 
concluded that in England there were two types of disease present: 
first of all, the contagious typhus; and, second, a sporadic disease 
identical with the typhoid fever of the French. It remained, 
however, for William Gerhard in 1837 to establish beyond doubt 
the differential criteria between typhus and typhoid fever, on the 
basis of his own experience in both diseases in France and in 
Philadelphia. Gerhard maintained that the typhus of Philadelphia 
was identical with British typhus fever and with the jail, ship, 
petechial or spotted fever, and that it is eminently contagious. 
On the other hand, the enteric or typhoid fever of the French is 
rarely communicated from one individual to another. He showed 
that the lesions of Peyer's patches and of the mesenteric glands 
invariably present in the latter were never found in the former, 
and remarked that English observers erred in regarding the in- 
testinal disease as a mere complication of typhus. He insisted on 
the marked difference between the petechial eruption of typhus 
and the rose-colored spots of typhoid fever, and he showed that a 
peculiar train of symptoms very different from those of typhus 
were associated with the intestinal affection, and that the dis- 
tinctive characters of the two diseases were such as should not 
allow them to be confounded in practice. Shattuck of Boston 
studied cases of both diseases in France and England and separated 
the two in London. Confirmatory observations were made by 
Valleix (1839) and by Rochoux (1840) in France, and by Barlow 
in England (1840). Sir W. Jenner l - 2 in London between 1849 and 
1851 further confirmed and amplified the distinction between the 
symptoms of the two diseases as previously laid down by Gerhard 



6 TYPHOID FEVER 

and others. By careful analysis of cases admitted into the London 
Fever Hospital, he showed that the two fevers did not prevail 
coincidently and that the one did not communicate the other. He 
also adduced cases to prove that an attack of either fever pro- 
tected the patient from subsequent attacks of the same malady but 
not from the other. Perhaps the most important bearing of these 
facts is their indication that the two diseases are not only different, 
but are due to distinct causes. 

It was possible, then, early in the nineteenth century to recognize 
typhoid fever as a disease entity on the basis of clinical observation 
and post-mortem examination. No clear understanding of the 
exact nature of the disease was, however, possible until the isolation 
of its specific bacterial cause, nor could the certain recognition of 
the disease in any particular case be assured in the absence of such 
knowledge. And, if the individuality and the recognition of 
typhoid fever is dependent on bacteriology, much more so is accu- 
rate knowledge concerning its method of transmission and effective 
prevention. 

DEVELOPMENT OF THE CONCEPTION OF CONTAGION IN TYPHOID FEVER 

There were, however, several observations in the pre-bacteriolog- 
ical days which were of extreme significance, and, indeed, of prac- 
tical importance in understanding and in controlling this disease. 
Up to the nineteenth century the general belief was that typhoid 
fever was not contagious. This relative non-contagiousness was, 
indeed, one of the earlier differential points in diagnosis between 
typhus and typhoid. Early in the nineteenth century, however, 
Leuret (1828), Gendron (1834), and Bretonneau (1829) in turn 
gave definite reasons for regarding typhoid as transmissible from 
one individual to another. In 1850 Piedvache summarized the 
facts, and concluded that the disease is to a limited extent con- 
tagious. In 1856 William Budd 1 began a series of publications on 
the nature and mode of transmission of typhoid fever, which con- 
stitute one of the most notable contributions to our knowledge of 
this disease. He not only proved conclusively by careful epi- 
demiological studies that the disease could be transmitted through 
the feces of a typhoid patient by means of water or milk con- 
tamination to healthy individuals, but repeatedly emphasized 
that this is the usual way in which the disease is propagated. He 
regards typhoid fever as contagious in the broader sense of the 
term, using Piedvache's definition that any transmission of a 
disease from a diseased individual to a healthy individual, what- 



GENERAL SURVEY 7 

ever may be the method, constitutes contagion. The poison of the 
disease, according to Budd, resides in the diarrheal discharges of 
the patient, and epidemics are usually caused by contamination of 
the water supply with such dejecta. "This method of reproduc- 
tion is not only a characteristic but the master fact in the history 
of typhoid fever," he says. He discards, after careful discussion, 
the putrefactive decomposition idea of Pettenkoffer and the 
pythogenic theory of Murchison, and shows that the disease is 
essentially self-propagating. He believes he was able to prove this 
method of contagion, owing largely to the fact that his practice 
was in the country, where such sewage contaminations are more 
likely to be traced than with the more complete methods of sewage 
disposal in cities. 

Budd, in addition, laid down definite rules which he proved to 
be effective in checking and preventing epidemics. It is very 
interesting, moreover, to find that he distinctly foresaw the possi- 
bility of spread of the disease from the dejecta of those who had 
entirely recovered from any active manifestations of the malady. 
In view of this now recognized, important carrier condition, it 
may be of interest to cite his exact words in this connection. Budd 
says (p. 118): "The precise date at which the fever patient ceases 
to give fever to others is not so easy to define. But I have seen so 
many instances in which fever has broken out in a family living in a 
previously healthy neighborhood soon after the arrival of a con- 
valescent, that I am quite sure that patients so far recovered can- 
not always be safely allowed to mix with others without precau- 
tion. In the case referred to all traces of actual fever had disap- 
peared and diarrhea had long ceased." 

Murchison 2 added certain additional facts to the contagiousness 
of typhoid fever through the feces, although his theory of trans- 
mission was marred by the introduction of the idea of a spon- 
taneous origin of the disease through fermentative processes out- 
side the body. He further subscribed to the importance of a 
transmission of typhoid by means of polluted milk. 

Of historical interest in this connection is the so-called ground- 
water theory of Buhl and of Pettenkoffer in reference to the spread 
of epidemics of cholera and typhoid fever. The theory, although 
no longer accepted in its entirety, doubtless throws some light 
on the spread of certain epidemics of these diseases. According 
to Pettenkoffer, the contagion of these two maladies would require 
a ripening stage in the earth, and the actual spread of the epidemic 
itself depends on the falling of the ground-water with consequent 
spread of these ripened contagia from the superficial water supplies. 



TYPHOID FEVER 



THE ADVENT OF BACTERIOLOGY AND ITS IMPORTANCE IN THE EX- 
PLANATION AND PREVENTION OF TYPHOID FEVER 

The year 1880 may be given as marking the advent of the science 
of bacteriology, and typhoid fever was one of the first of the human 
infectious diseases to yield the secret of its specific animate causa- 
tion. In the few years preceding 1880 several observers had de- 
scribed the occurrence of certain micrococci in the tissues of cases 
of typhoid fever. The bacillus, however, which we now recognize 
as the cause of the disease was not discovered until 1880. The 
first observations of Bacillus typhosus in the tissues may be attrib- 
uted to three independent investigators, namely, Eberth, Klebs, 
and Koch. Credit of priority in the discovery of the micro- 
organism is generally given to Eberth, but it may well be that 
injustice has been done in the general acceptance of this priority. 
It is of interest, therefore, to examine the investigations of these 
authors in some detail. On April 22, 1880, appeared the first 
contribution of Klebs l on the nature of typhoid, in which he 
describes his findings in twenty-four fatal cases of the disease. 
In each of these cases he found short rods, and also in certain 
places filamentous but unbranching bacterial structures in the 
various tissues of the body which are peculiarly associated with 
the malady. He found these organisms in Peyer's patches, in 
the mesenteric lymph nodes, in the blood vessels, and also in the 
pia of certain meningeal cases of the disease. The organisms 
were not found in the intestinal wall of normal cases. They were 
found in definite relation to what he describes as "a leucocytic 
proliferation" in the necrotic areas caused by the disease. 

In July of the same year Eberth ! published his findings in 
typhoid. In the majority of cases of the disease which he inves- 
tigated he found short bacterial rods in various organs of the body, 
which diminished in number with the progression of the disease. 
He states that these rods at times possess spores and do not stain 
well with the ordinary aniline dyes. From the illustrations which 
accompany his article it would appear certain that he was dealing 
with the Bacillus typhosus, although the sporogenous forms which 
he likewise depicts are misleading. In the year 1881 Koch l 
published photomicrographs of the bacterial findings in various 
infectious diseases, among them typhoid fever, in which the 
characteristic microorganism appears with convincing clearness. 
Both Eberth 2 and Klebs agree that the bacterial or rodlike forms 
which each of them had in turn described are identical. The 



GENERAL SURVEY 9 

difference in their findings would seem to rest in the description 
by Klebs of threadlike forms of from fifty to eighty micra in length, 
which we do now recognize as characteristic of the growth of the 
typhoid bacillus, at least in the body. Somewhat similar forms 
have been described in culture media. This type Klebs regards 
as a second stage in the development of the rodlike form. Klebs 
may well have erred in describing a type of microorganism which 
may have been a secondary invader; it is evident, however, that 
he really did see the same typhoid bacillus that Eberth describes. 
Since criticism is made of his description of this threadlike micro- 
organism, it may also be pointed out that the sporogenous micro- 
organism described by Eberth is likewise inaccurate. At all 
events, the threadlike forms described by Klebs seemed to him 
subsidiary to the rods which alone are mentioned as occurring in 
the various organs of his twenty-four protocols. Klebs unques- 
tionably should be credited with suggesting the accepted name 
(B. typhosus) for the etiological agent in typhoid fever. 

It would seem also that at least some credit should be given to 
Klebs for his attempt, and, perhaps, success in cultivating Bacillus 
typhosus outside of the animal body, although the usual credit 
for this discovery is given entirely to Gaffky (1884). In Klebs' 
second communication in 1881 2 he describes his method of pre- 
paring and sterilizing gelatine culture media, his inoculation of 
such media from the mesenteric lymph nodes of a case of typhoid 
fever, and he further notes the occurrence of rodlike forms in the 
turbid culture growth which results from the inoculation. Gaffky 
objects to accepting Klebs' results largely on the basis that he had 
described threadlike forms as existing in the disease, and also 
owing to the fact that he, Gaffky, failed to produce lesions in 
animals with his pure cultures similar to those that had already 
been described by Klebs. Klebs had described the production 
of hemorrhagic infiltration without ulceration in the cecum of 
rabbits following injection of his culture of the microorganism. 
Although Gaffky failed to obtain such results with his cultures, 
it is now known that they may be produced with pure cultures 
and toxins of the typhoid bacillus, although they are not specific 
in nature (Arima, 1 Gay and Clay pole x ). Klebs, then, may well 
have grown Bacillus typhosus and, indeed, may have grown it in 
pure culture, although it remained for Gaffky to demonstrate 
the purity of the culture, as he was able to do by the employment 
of solid culture media. Gaffky remarks on the absence of spores 
in his artificial cultures of the microorganisms, and also comments 
on its growth on gelatine and potato. 



10 TYPHOID FEVER 

We have discussed hitherto in some detail the historical de- 
velopment of our knowledge concerning typhoid fever, first on 
purely clinical grounds, and secondly, on the ground of post- 
mortem examination. We have further considered the early 
observations of the typhoid bacillus in the tissues and, secondly, 
the growth of this microorganism in pure culture. We may now 
proceed to outline rapidly the successive advances which have 
followed the complete recognition of a single etiological factor in 
this disease, leaving more detailed consideration of the method of 
obtaining such facts and of their significance and applicability 
to subsequent chapters. It will, we believe, be evident that all 
significant information concerning the nature of the disease itself 
and its method of dissemination, as well as all effective means 
that have been devised to prevent and cure it, have depended on 
laboratory data and are based on the recognition of the single 
bacterial causative factor. 

Following the observations of Klebs, Eberth, Koch and Gaffky 
that the typhoid bacillus occurs in the various organs that are 
obviously affected in the disease, and can be isolated from them 
in pure culture, it was soon shown by A. Pffeiffer (1885) that the 
organism could also be found in stools, and by Hueppe 1 in the 
following year in the urine in typhoid fever. 

One of the most important landmarks in the development of 
our knowledge concerning typhoid fever and in its diagnosis is 
the detection of the causative microorganism in the circulating 
blood. Fraenkel and Simmonds 1 (1886) are usually credited with 
this important discovery. They isolated the organism, to be sure, 
from the blood of the cadaver in one of six fatal cases in that year, 
but failed then and the year before to obtain it from the blood of 
living cases. The presence of the microorganism in the blood post 
mortem, is of course, of interest, but might well be due to a terminal 
invasion, and for both diagnostic and etiological reasons the greater 
importance attaches to the discovery of the bacillus in the blood 
intra vitam. It is apparently Vilchur who in 1887 was first suc- 
cessful in isolating the typhoid bacillus from the circulating blood, 
although only in one of thirty-five attempts. Neuhaus had in the 
previous year obtained the organism from the blood of rose spots 
in nine of fifteen cases. 

It is now generally recognized that typhoid fever is primarily 
a bacteremia and not a disease essentially characterized by in- 
testinal lesions, which, although they occur in a majority of cases 
must be regarded rather as incidental and terminal than indica- 
tions of the true nature of the disease itself. It has already been 



GENERAL SURVEY 11 

pointed out by Louis and others on purely clinical grounds that 
cases of apparent typhoid fever might occur with absence of any 
lesions in the intestines. That such cases were indeed typhoid 
fever and not some disease simulating it, remained, however, to 
be proven in cases that could be bacteriologically controlled. 
Such an observation was first made apparently by Terrile, who 
described a case of typhoid from which he isolated the bacillus 
in the blood and which showed at death no intestinal lesions. 
Numerous similar cases have since been described by Chiari * 
and others. 

Of great significance was the isolation in 1890 by Gilbert and 
Girode x of the typhoid bacillus from the gall bladder in cases of 
typhoid with acute cholecystitis. Chiari 2 showed a few years 
later that the microorganism occurs with great regularity in this 
viscus during typhoid fever. The relation of these observations to 
our knowledge of the course of the disease and of its sequels will 
be fully considered in another place. 

By the year 1890, then, it was generally recognized that no 
disease could properly be called typhoid fever unless the typhoid 
bacillus was found somewhere in the body; and, conversely, any 
case having such an organism in the body, or at least in the blood, 
must be one of typhoid fever.* Another and almost equally val- 
uable method of differential diagnosis was introduced into practice 
by Widal 1 in 1896. The characteristic property he found in the 
blood serum of typhoid cases depends upon the important phe- 
nomenon of agglutination. A clumping occurs when the serum 
of animals that have been inoculated with or infected by a given 
bacterium is allowed to act on the provocative microorganism. 

In the year 1896, Achard and Bensaude reported the first cases 
which led to separating from the typhoidal fevers a group of 
maladies now known as paratyphoid infections, similar in most 
respects clinically to the fever caused by Bacillus typhosus, but 
each due in turn to a specific microorganism of the paratyphoid 
or paracolon group. Such organisms, differing in their sugar reac- 
tions from true typhoid bacilli, were described in two cases by 
these French authors and were found in one instance in the urine, 
and in the other in a parotid abscess. In the following year, 1897, 
Gwyn isolated a similar "paracolon" organism from the circulat- 
ing blood of a case, the serum of which agglutinated this organism 
but not the typhoid bacillus, and thereby proved its etiological 
relation to the disease. 

In the year 1893, Fraenkel made the first attempt to affect 

* Exception must be made to the healthy or recovered bacillus carriers. 



12 TYPHOID FEVER 

typhoid fever in a specific manner by the subcutaneous injection 
of killed cultures of the typhoid bacillus. In 1896, preventive 
inoculation against typhoid fever was independently attempted by 
Sir Almoth Wright x and by Pfeiffer and Kolle. 1 

Attention may now be drawn to certain observations of sig- 
nificance in relation to the spread of typhoid fever. Reference 
has already been made to the suggestion of Budd concerning con- 
tagion from recovered typhoid cases, and the observations of 
Klebs 3 in 1887 likewise indicate the danger of infection from the 
feces of afebrile cases or even of healthy individuals. The danger 
of feces from cases of typhoid fever in spreading the disease was 
convincingly pointed out by Reed, Vaughan and Shakespeare in 
their study of the typhoid epidemics in the Spanish-American War 
(1898). In their report they point out that the spread of the dis- 
ease in certain regiments bore an undoubted relation to the care- 
lessness in erecting privies, the exposure of dejecta and the prob- 
able role of flies that had access to these dejecta in contaminating 
food supplies. Several observers had shown that flies could me- 
chanically carry bacteria for varying periods of time, and Hamil- 
ton finally completed the chain of evidence by showing that flies 
captured in houses in which there were cases of typhoid actually 
did carry typhoid bacilli. 

In 1898, Petruschy suggested that people who had recovered 
from typhoid fever might still be able to infect healthy individuals 
by means of typhoid bacilli that persisted in their urine. Robert 
Koch (1903) 2 deserves credit for first specifically calling attention 
to the danger of the extension of typhoid fever through typhoid 
bacilli in the excreta of convalescents, or possibly of persons who 
were apparently healthy. This suggestion was confirmed by 
Frosch in epidemics in southwest Germany, and led to the es- 
tablishment of many stations there for the study of such ways of 
disseminating the disease. This study proved not only the rela- 
tive infectiousness of stools in different periods of the active dis- 
ease, but demonstrated that the bacilli persist for varying lengths 
of time in some four per cent of recovered cases. In 1904, Dri- 
galski made the important observation that typhoid bacilli may 
also be found in the feces of some individuals who have apparently 
never suffered from the disease and that epidemics may be caused 
by such "healthy" carriers. 



CHAPTER II 

TYPHOID FEVER AS A CAUSE OF DEATH AND 
DISABILITY 

Our interest in typhoid fever is manifold and compelling. In 
the first place, we are humanely concerned with the disease as 
one of the great causes of death and disability, more particularly 
in the past, but yet to a considerable extent in the present. And 
it is precisely this rapidly waning seriousness of typhoid that en- 
hances its interest as a pragmatic problem of preventive medi- 
cine. The rapidly increasing group of facts that has been gathered 
through its scientific study, and particularly during the latter 
years, has led not only to a gratifyingly complete conception of 
the disease process itself, but has produced practical results of 
great significance. No human disease, under varying conditions 
of fife, in war and in peace, has been more rapidly checked, and 
none gives greater promise of eventual complete suppression. 

THE SIGNIFICANCE OF TYPHOID FEVER IN MORTALITY STATISTICS 

In the United States, of all nations, our consideration of the 
typhoid problem is particularly to be desired, since we have 
hitherto been extremely backward in applying recognized methods 
of sanitary prevention which have long prevailed in other lands. 
Typhoid fever remains the ninth contributing cause to the mor- 
tality statistics * in this country and ranks fifth among the infec- 
tious diseases, being exceeded as a cause of death only by tuber- 
culosis, pneumonia, infantile diarrhea and diphtheria. The eco- 
nomic importance of the disease is even greater than is suggested 
by these mortality figures, serious as they are, for it is precisely 
in those years of greatest expectancy and promise that its in- 
cidence is greatest. After passing through the perilous years of 
infancy with its characteristic and as yet not wholly avoidable 
infections, the child, and particularly the young adult, arrives 
at a period where his chances of usefulness are found to be most 
assured, and it is during this period that typhoid is most common. 
About fifty per cent of all cases of the disease occur between the 
ages of fifteen and twenty-five, and the greater part of these in 
* Dept. of Commerce Mortality Statistics, 1915. 
13 



14 TYPHOID FEVER 

the earlier lustrum (Murchison; 1 Curschmann) . Graham, who 
has studied the incidence of acute infections occurring in children 
in Philadelphia from 1911 to 1915, finds that typhoid fever ranks 
next to diphtheria as a cause of death and has the highest mor- 
tality rate. 

The actual death rate from typhoid in the United States was 
in 1900, 35.9 to the 100,000 inhabitants, and in 1913, 17.9, an 
encouraging diminution of over fifty per cent. Most of the 
other major causes of death have also diminished during this 
period, with the exception of cancer and certain chronic diseases, 
but the rapidity of diminution in typhoid fever has been exceeded 
by only one other acute infectious disease, namely, diphtheria. 
Any satisfaction we may feel in these results is, however, lessened 
on considering that our mortality rate in 1900 had not quite 
reached the low level in Germany in the five years from 1879 to 
1883. The actual number of cases of typhoid fever in the United 
States in the year 1900 is estimated at 353,790 (Whipple), and the 
deaths were 35,379. In 1914, the number of cases had diminished 
to 198,000 and the deaths correspondingly to 19,800 (Dublin). 
In 1912, the death rate in Germany * was three per 100,000, or 
actually 2,119 deaths, in a population of over 64,000,000. There 
may be some satisfaction in finding that the United States re- 
cently shows a lower typhoid death rate than the two most back- 
ward continental nations, Spain and Italy, which in 1912 were 
twenty-seven and twenty-two respectively. No other European 
nation, however, exceeded nine (Belgium). 

The occurrence of any given disease in a community is usually 
estimated from the mortality statistics and not from the actual 
cases that are supposed to exist. In the case of typhoid the death 
rate is more accurate and complete, owing to possible errors in 
diagnosis and failure to report cases that do not terminate fatally. 
It is, therefore, important to know the percentage mortality 
which is ordinarily to be expected, and it is generally accepted 
that in typhoid fever the mortality is now about ten per cent. 
It is interesting in this connection to note that the mortality rate 
fell markedly in the latter half of the nineteenth century. In 
Murchison's statistics from the London Fever Hospital it appears 
that for the twenty-three years from 1848 to 1870 the mortality 
varied between 15.63 and 26.97 per cent, the latter figure being 
the one for the year 1848. The average for this period was 17.26 
per cent. This may further be compared with statistics which 

* Ergebnisse des Todesursachen Statistik im deutschen Reich fur das Jahr 
1912. Springer, Berlin, 1914. 



TYPHOID AS CAUSE OF DEATH AND DISABILITY 15 

Murchison gave from the best hospitals in France, Germany and 
England, which gave a similar average mortality of 17.45 per 
cent. It is evident, then, that the decrease in mortality, which is 
due in large part to better care and probably also to lessened 
virulence of the infection for the individual, or conversely to in- 
creased human resistance to this particular disease, must be taken 
into consideration in estimating the diminution of the disease 
itself from the mortality statistics. The tendency then in more 
recent statistics, based on the decreasing mortality rate, is to 
underestimate the actual number of cases of the disease. It may 
be noted here that the mortality percentage increases with the 
age of the patient, ranging from a little over two per cent in in- 
fants to thirty-five per cent in adults over forty-five years of age. 
The mortality is undoubtedly higher in hospitals than it is in 
those private houses where the best facilities for nursing are avail- 
able (Jochmann; Brouardel and Thoinot). 

CHRONOLOGICAL CHANGES IN THE TYPHOID DEATH RATE 

The chronological diminution of typhoid fever has already been 
suggested. We may express this diminution somewhat more con- 
cretely by taking first certain figures collected by Seitz 1 in Ger- 
many towards the end of the nineteenth century (Table I). 

TABLE I 

COMPARATIVE MORTALITY STATISTICS FROM TYPHOID FEVER PER 100,000 OF 
POPULATION IN GERMANY, BAVARIA AND MUNICH AT SUCCESSIVE PERIODS 

Germany Bavaria Munich 

1857-67 — 77 203 

1868-78 47 54 123 

1879-83 26 26 30 

This table, which is representative of many other statistics col- 
lected over a similar period, illustrates two important facts from 
which a great hygienic principle of particular import in typhoid 
fever and some similar diseases may be deduced. It will be noted, 
first, that the mortality rate during the greater part of this period 
was consistently and markedly higher in a city than in the state or 
empire at large, and, secondly, that a sharp diminution in both city 
and empire occurred about the year 1880. This diminution, it 
may be noted, continued until in the period 1901-1910 the mortal- 
ity rate for Munich averaged 2.5 to the 100,000. 

From these and other similar figures the general statement may 



16 TYPHOID FEVER 

be made that prior to a period, roughly about the year 1880, 
typhoid fever was a disease the incidence of which varied directly 
with the density of population, as shown by the increased number 
of cases in a city like Munich as compared with the larger districts 
of which it formed a part. Further mortality statistics from the 
same city of Munich, comparing the incidence of the disease in the 
Munich garrison as against the general city population, still further 
and in a more concrete manner illustrate the same principle 
(Table II). 

TABLE II 

COMPARATIVE MORTALITY STATISTICS IN THE MUNICH GARRISON AS COMPARED 
WITH CITY MORTALITY (FROM SEITZ) 



City 


Garrison 


S69 204 


840 


181 57 


190 



The great menace which typhoid fever has always been to 
armies, both in peace and war, is a matter which will be considered 
separately at a later point. 

We are concerned at this point not so much with this interesting 
and striking diminution in the mortality rate itself, as with the 
causes which underlie it. These causes are, first, the full recogni- 
tion of water contamination from sewage as the source of trans- 
mission in typhoid, as had been pointed out some years before by 
Budd, 2 and the consequent introduction of pure and safeguarded 
water supplies. And, second, the re-emphasis and rendering con- 
crete of this first fact when transmission of the disease became 
typified in its recognized parasitic cause. The recognition of the 
etiologic importance of a specific bacillus of typhoid fever not only 
gave greater impetus in protecting water supplies from the dejecta 
of typhoid patients, but led undoubtedly to greater circumspection 
in handling the patients themselves and a consequent diminution 
in contact infections. 

We may now consider in more detail the direct effect of the 
purification of water supplies on the mortality incidence of typhoid 
fever, particularly as it occurs in cities. This may be shown in two 
different ways: first, by comparing the incidence of the disease as 
it occurs in cities grouped in accordance with the purity of their 
water supplies; secondly, by comparing the incidence of the 
disease in any given city before and after any marked improve- 
ment in the water supply (Kober). 



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TYPHOID AS CAUSE OF DEATH AND DISABILITY 17 

These two graphic illustrations show clearly the relation of 
purity in water supply to the incidence of typhoid fever. It is 
evident first (Fig. 1) that the purer the water supply in cities the 
less the incidence of the disease. In Fig. 2 it is shown that a change 
from a contaminated to a purer water source in any given city de- 
creases the mortality at once. Owing to the close relation that 
exists between water supply and typhoid, the disease has been 
referred to by Sedgwick as a correct "sanitary index" of purity of 
water and food supplies. 

We have seen, then, that typhoid fever was formerly a disease of 
crowded communities, occurring with greater frequency in cities 
than in the country, in crowded than in less crowded communities, 
and we have seen that a diminution in the mortality from this 
disease takes place in direct relation to the purity or the purifica- 
tion of water supplies. We may now consider more recent figures 
in reference to the occurrence of the disease in the large cities of 
Europe and of the United States. 

TABLE III 

COMPARATIVE MORTALITY STATISTICS OP TYPHOID FEVER IN CITIES OF 
CONTINENTAL EUROPE AND UNITED STATES 

Population Mortality Average 

33 largest European cities 31,500,000 1901-1910-6.5 

57 largest American cities 21,000,000 1910-19.59 

In the first line of Table 3 is given the mortality average of 
typhoid fever during the decennial period from 1901 to 1910 in the 
thirty-three largest European cities with an aggregate population 
of 31,500,000. It is seen that the average mortality is extremely 
low, namely, 6.5 per 100,000 of population, and it is the more 
surprising when we consider that cities like Stockholm, the average 
of which is 1.7 for this period, are placed in the table, and also such 
cities as St. Petersburg, which has a mortality of 33.7 per 100,000 
owing to the drinking of contaminated river water in the city. 

It is interesting to compare with these European figures those 
for fifty-seven of the largest American cities with an aggregate 
population of 21,000,000. It is seen here that not only does the 
mortality exceed that of European cities by more than three 
times, but the figure for the American cities is taken at their very 
best, namely, at the last year of this period. 

A further consideration of the American figures in still more 
recent years will be of interest at this point. In Table IV are 
considered the mortality statistics of typhoid fever in, first, the 



18 



TYPHOID FEVER 




Fia. 2 



zg. Area 


U. S. Army 


33.8 


— 


21.1 


28 


23.5 


16 


21 


11 


16.5 


3 


17.9 


— 



TYPHOID AS CAUSE OF DEATH AND DISABILITY 19 

fifty-seven largest cities of the United States; second, the total 
registration area of the United States, which comprises twenty- 
seven states and approximately two-thirds of the total population; 
and, third, the figures in the United States army. 

TABLE IV 

INCIDENCE OF TYPHOID IN 57 CITIES OF THE UNITED STATES COMPARED WITH 
TOTAL REGISTRATION AREA AND THE UNITED STATES ARMY 

Cities 
1900-1904 

1909 

1910 19.59 

1911 15.74 

1912 12.56 

1913 12.77 

This table shows not only a gradual diminution in the death 
incidence in all three categories considered, but, what is more 
interesting, shows a complete reversal of form in relation to the 
disease incidence in rural and city communities that we have 
presented as characteristic in European cities in an earlier period. 
This change is chronological and not local, for whereas formerly 
the disease was primarily one of crowded communities, it is found 
now to be a disease of rural communities. Fulton has shown, in- 
deed, that in five states of which the urban population was sixty 
per cent of the total, the average death rate of typhoid was twenty- 
five per 100,000, whereas in twelve states with an urban population 
which reached only ten per cent of the total, the average death rate 
was sixty-seven per 100,000. This change in typhoid mortality as 
between city and country is concretely illustrated in the Report of 
the New York State Department of Health for 1914, which graph- 
ically contrasts the mortality in New York City with that of the 
rural community of New York State as shown in Figure 3. 

This figure shows a marked and nearly unbroken decrease in the 
city death rate between 1900 and 1914 of from 20.6 to 14 per 
100,000, whereas the rural figures have remained stationary during 
the same period and have thereby come to exceed the city rate. 
This reversal of figures, however, is equally attributable to the 
same basis as the previous ones, namely, a purification of water 
supplies, because sewage disposal and water purification are now 
far better safeguarded in cities than they are in the country. 

* Russell: 1 The sharp diminution in the U. S. army in 1912 is due to the 
introduction of vaccination in this vear. 



20 



TYPHOID FEVER 



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TYPHOID AS CAUSE OF DEATH AND DISABILITY 21 



TYPHOID FEVER IN ARMIES 

Appalling as has been the death rate from typhoid fever in civil 
communities, particularly in large cities, it was still greater in 
armies, as has already been indicated in Table II, and here again 
the same rule holds, the greater the density of the population the 
greater the incidence of the disease, owing in part to the contamina- 
tion of the water supply; and, conversely, with purification of 
water supplies, the diminution in crowded and congested districts 
becomes rapidly less. Of almost equal significance in armies, 
prisons and asylums is the contamination of common food supplies 
by flies and human carriers, both matters which we shall consider 
in their proper place. In Table V we consider further mortality 
statistics from the Munich garrison over a period of years bearing 
obvious relation to a purifying of the water supply, which took 
place in 1880. 

TABLE V 

REDUCTION OP TYPHOID MORTALITY IN MUNICH GARRISON 

1851-1860 1110 per 100,000 

1861-1870 567 " 

1871-1880 466 " 

1881-1890 19.8 " 

The figures for the entire French and German armies during a 
similar period, not including the years during which the army was 
engaged in actual warfare, show similar results. Glenard has 
shown that from 1875 to 1880 there was an annual morbidity from 
typhoid in the French army of 380 to the 100,000. In the French 
army during this period typhoid fever was the cause of thirty-six 
per cent of all the deaths that occurred. ]^o attention was paid to 
hygiene and water filtration in the French army until the year 
1888, at which time it was estimated by the Minister of War, de 
Freycinet, that a reduction of thirty-six per cent in the number of 
cases took place in a single year as compared with the three pre- 
vious years, and in the following year the reduction was forty-nine 
per cent. As indicating the extremes following sanitation, Kossel l 
mentions that typhoid in the German army produced a death rate 
in 1869 of 170 to 100,000; in 1909-1910 it had fallen to eight. 

The figures for typhoid in armies under conditions of actual 
warfare are still more astonishing and have frequently been quoted. 
For example, during the American Civil War there are estimated 



22 TYPHOID FEVER 

to have been 75,361 cases of this disease with 27,056 deaths. In 
the Franco-Prussian War there were 73,396 cases with 8,786 
deaths, the latter supplying sixty per cent of the total mortality 
during this period. Even in recent times similar disgraceful figures 
have occurred, owing to the carelessness in camp hygiene and to 
the difficulty of securing a constant pure water supply. During 
our Spanish-American War in a force of 107,973 troops there 
were 20,738 cases of the disease with 1,580 deaths, constituting 
eighty-six per cent of all who died of disease (Whipple). These 
cases occurred peculiarly in camps that were more or less per- 
manent and in the concentration camps, and one man in every 
five enlisted contracted typhoid fever. In the South African 
War in a force of 557,653 officers and men there were 57,686 cases 
with 8,225 deaths, whereas during the same war the deaths from 
wounds were only 7,582. The fact that armies are composed for 
the most part of healthy men of the exact age period which shows 
greatest susceptibility to typhoid is another contributing cause 
to the high army morbidity. 

THE PRESENT ECONOMIC LOSS FROM TYPHOID 

It is evident, then, from these summarized statistics that 
typhoid fever has been a disease of appalling frequency, the fre- 
quency until recent years varying directly with the density of 
the population and being due in large part to contamination of 
the water supply. With purification of the water supply and 
proper sanitation the mortality and morbidity from this disease 
have been remarkably diminished. In America, however, we have 
been extremely backward in proper appreciation of this menace 
and of the relative ease with which it can be checked, but even in 
Europe where greater precautions have been taken for a longer 
period of time, it has not been possible, particularly in the rural 
districts where typhoid fever is now more prominent, entirely to 
obliterate it. 

This residuum of cases, particularly in the rural communities, 
is now found to be referable not so much to failure rigidly to safe- 
guard water supplies as to other methods of transmission of the 
disease. After removing the large group of water contamination 
cases, which formerly monopolized the attention, it has become 
evident that another considerable number are due to contact in- 
fection, particularly through carriers. Vigorous efforts have been 
made in Germany to particularize and to obliterate these sources 
of infection. But these and other methods of infection as well 



TYPHOID AS CAUSE OF DEATH AND DISABILITY 23 

as more recent measures of prevention, as through vaccination, 
can more logically be considered in other connections. 

Let us consider finally just what the significance of typhoid 
fever is in the United States at the present time and what economic 
loss it entails. 

In 1900, there were in our country approximately 350,000 cases 
of typhoid fever, as has already been mentioned, and the cost to 
the community of this number of cases has been estimated by 
Whipple to have been something like $212,000,000. Whipple 
found this surprising total by evaluating an adult life at $4,634, 
which, with the total cost through disability for those cases that 
did not die, bring the total for each death to a loss to the com- 
munity of something like $6,000. In a more recent estimate of 
the cost of typhoid fever in epidemics in Pittsburgh, which re- 
curred for several years and mostly among the poorer classes, 
Wing has computed the value of each death to the community 
at something like $4,000, which he states is a very moderate es- 
timate. The cost of each case for loss of wages, treatment, and 
nursing is in addition $128. On this basis the 198,000 cases 
(Dublin) which occurred in the United States in 1914, and the 
corresponding 19,800 deaths would have cost the United States 
for that year $104,544,000. 

Another feature of typhoid fever in addition to the actual deaths 
that occur during the course of the disease is the lessened resistance 
for a certain period of time in those individuals that recover. 
Dublin has recently estimated that the incidence of mortality in 
typhoid recovered cases for the subsequent three years is over 
twice that among normal individuals. If the normal expectation 
of death for each of these three years is taken as one hundred, 
the expectation in typhoid convalescents is two hundred and four. 
On the basis of the typhoid incidence and deaths in 1914, as al- 
ready computed by him, there must have been 178,200 recovered 
cases, and the extra deaths in these individuals attributable to 
the antecedent typhoid was 7,781. This would raise the national 
bill for this largely preventable malady for a single and recent 
year (1914) to $135,678,000. 

The mortality danger in typhoid comprises not only those 
deaths due to primary typhoid infection or toxemia per se, but 
an even larger number due to the accidents and complications of 
the disease. Dopfer estimates that over seventy-five per cent 
of the fatalities are due to such causes. This tendency to com- 
plications, which is one of the characteristic features of the malady, 
in addition to their potential danger, adds still further to the dis- 



24 TYPHOID FEVER 

tress, prolonged disability and cost to the individual. It would 
be impossible to estimate in what per cent of cases one or more 
of these complications occur. The percentage of deaths due to 
complications and also the percentage of cases in which each 
complication occurs, have both been estimated repeatedly. If 
we add together the percentage of occurrence of each of the major 
complications we find that several accepted lists will total over 
thirty per cent. This total is given with all reserve as to its actua 1 
significance, but is indicative of the frequency with which such 
untoward results occur in typhoid fever. 

No attempt to indicate the severity of typhoid fever would be 
complete without some reference to the long duration of the dis- 
ease itself. Apart from any complications or sequels, the fever 
itself lasts in even the mildest cases on an average of twenty-one 
days or more, extending in many of them to over thirty-three 
days (Curschmann). In McCrae's 1,500 cases the general aver- 
age of the febrile period was 29.4 days and the actual period dur- 
ing which the patient was hospitalized was forty-nine days. 



CHAPTER III 
THE TYPHOID BACILLUS 

BACILLUS TYPHOSUS AS THE CAUSE OF TYPHOID FEVER 

The typhoid bacillus (Bacillus typhosus), first described in the 
organs of cases dead of typhoid fever by Klebs, by Eberth, and 
by Koch (1880), and first grown in pure culture by Gaffky (1884), 
may now be unreservedly accepted as the certain and single cause 
of the disease from which it derives its name. It may be obtained 
from the rose spots, circulating blood, stools, and urine during life, 
and from the characteristically affected organs after death in all 
cases of typhoid. It may be grown in pure culture and differen- 
tiated from similar organisms by means of appropriate media. 
The blood serum of cases of typhoid fever has the specific prop- 
erty of clumping typhoid bacilli, which property is not possessed 
by normal sera or sera from those suffering from other diseases. 
Typhoid serum exerts no effect on other bacteria, thereby further 
proving a causative relation between the bacillus and the disease. 
The typhoid bacillus is never found in normal individuals or in 
other diseases, except in a few recovered cases and in those rare 
instances of healthy carriers who, though themselves unaffected 
by the disease, may harbor the organism and transmit it to others. 

It may further be shown that B. typhosus is the cause of typhoid 
fever in those cases which have followed accidental or intentional 
ingestion of pure cultures of the microorganism, and, finally, 
typhoid fever has been reproduced in all essential particulars in 
chimpanzees by feeding them with food containing a generous 
admixture of typhoid cultures or by smearing their mouths with 
such growths. These latter experiments, which we owe to Met- 
schnikoff and Besredka, 1 and to which we shall refer in more de- 
tail in another place (Chapter V), showed, moreover, that it is 
in reality the typhoid bacillus itself and not some adherent filtrable 
virus that produces this characteristic malady. 

THE CULTURAL CHARACTERISTICS OF BACILLUS TYPHOSUS 

We may proceed, then, to the consideration of the charac- 
teristics of the microorganism. The typhoid bacillus has been 

25 



26 TYPHOID FEVER 

studied extensively, not only as the cause of a very important 
disease, but because it is difficult to differentiate from similar 
pathogenic bacteria and particularly from the colon bacillus, which 
is the normal and predominating inhabitant of the intestinal 
canal. 

The typhoid bacillus stains readily either in tissues or in culture 
preparations with the ordinary aniline dyes. It is decolorized by 
Gram's method. It appears as a short, plump rod, varying in 
length from one to three microns and in thickness from 0.5 to 
0.8 microns, being somewhat longer in fluid than on solid media. 
In old gelatine and potato cultures it may grow in chains or fila- 
ments of considerable length. In recent cultures the stain is ab- 
sorbed uniformly, but in old cultures the protoplasm may stain 
somewhat irregularly. 

The bacillus is usually actively motile in young bouillon cul- 
tures, particularly in dextrose bouillon or when suspended from 
fresh cultures on solid media; the motility may, however, be tem- 
porarily lost in old cultures or when the medium is too alkaline. 
The colon bacillus is less characteristically motile than Bacillus 
typhosus. The flagella which are present in both organisms also 
differ in their distribution and number. In Bacillus typhosus the 
flagella are arranged peritrichously and are eight to twelve in 
number, and measure six to eight microns in length; in Bacillus 
coli they are grouped at the ends and are usually only two or four, 
but may be more in the more motile strains. The typhoid bacillus 
does not produce spores. 

Capsules have recently been described surrounding the typhoid 
bacillus by Kuhnemann and by Carpano. We have readily suc- 
ceeded in repeating their results in various strains of the organism 
grown on different media (Gay and Claypole 2 ). The clear zones 
which surround the bacteria when properly stained would seem, 
moreover, to be an actual part of the bacterial body and not arte- 
facts, as judged from the careful studies of Marassini and Shimidsu. 

Typhoid bacilli, when obtained from uncontaminated sources 
in cases of typhoid fever, or when derived from pure cultures, 
disseminated and poured in fluid agar or gelatine, grow readily 
and in a characteristic manner. On agar the surface colonies are 
thin, nearly transparent, and filmy; on magnification they are 
finely granular in appearance, are crenated and have well defined 
margins. Deeper colonies are lenticular or spherical and opaque. 
In gelatine the growth is naturally slower, the deep colonies are 
yellowish-brown in color and resemble those of Bacillus coli. On 
the surface they are bluish-white and leaf-like in character. The 



THE TYPHOID BACILLUS 27 

colon colonies are larger in general than typhoid colonies. The 
typhoid bacillus does not liquefy gelatine. 

In common with other members of the colon-typhoid group the 
typhoid bacillus grows readily in ordinary culture media but less 
actively than Bacillus coli. It nourishes best at body tempera- 
ture, but will grow in a range roughly of from 8°C. to 43 or 44°C 
It grows both aerobically and anaerobically. A temperature of 
60° for ten to twenty minutes or of 100° for three minutes will 
kill the bacillus, but the resistance is greater when the bacilli are 
cloaked in such organic matter as feces. The majority of or- 
ganisms when added to drinking water die in a few days whereas 
they multiply rapidly in milk. The typhoid bacillus will with- 
stand low temperatures for a time, and even freezing, but tends 
to disappear rapidly in ice, nearly all the organisms being dead 
at the end of two weeks (Park and Williams). Typhoid bacilli 
are somewhat more susceptible to disinfectants than colon bacilli. 

In bouillon Bacillus typhosus grows readily and uniformly and 
almost always without forming a pellicle, which, however, may 
occur when the medium is sufficiently alkaline. On agar and gela- 
tine the growth of the organism is not distinctive, and similar to 
if somewhat less profuse than the colon bacillus. 

Under proper conditions the growth of Bacillus typhosus on 
potato is differential from B. coli; in younger potatoes, where 
the reaction is acid, the growth of the typhoid bacillus is nearly 
invisible. The colon bacillus is cream colored or brownish and 
obvious; in older alkaline potatoes this distinction between the 
two cultures is lost, but the original conditions may be restored 
by adding a small amount of organic acid. According to Vincent 
and Muratet, whose statement we have readily confirmed, Bacillus 
coli rapidly produces a green color when grown on artichokes, 
whereas the typhoid bacillus does not. 

The growth of Bacillus typhosus in litmus milk is characteristic 
and marked by little chemical change. In most instances a slight 
acidity is produced which is permanent, although in a few in- 
stances strains of typhoid may produce an initial acidity followed 
by return to an alkaline reaction which remains permanent. The 
milk is not curdled. In sharp distinction, Bacillus coli produces 
marked acidity and rapid coagulation of the milk. The acidity 
produced by Bacillus typhosus in milk is equivalent to less than 
three per cent of one- tenth normal acid, whereas that produced by 
Bacillus coli is seven per cent or more. In the case of the typhoid 
bacillus the acid comes from the small amount of dextrose and 
not from the lactose of the milk. 



28 TYPHOID FEVER 

Bacillus typhosus in contradistinction to Bacillus coli does not 
produce indol in peptone water solution. It may, however, under 
artificial conditions of growth in rich peptone media be trained to 
do so. 

According to Kendall, the typhoid bacillus liberates ammonia 
from protein in sugar-free media and also forms small amounts 
of non-soluble alkaline products as well. The reaction therefore 
becomes alkaline. When sugar is present the reaction is acid, 
owing to its fermentation, and the protein is not attacked. The 
acids formed are chiefly lactic acid with small amounts of formic 
acid. Most important in the identification of Bacillus typhosus 
and particularly in its differentiation from Bacillus coli and from 
intermediate organisms are the sugar reactions. In contradis- 
tinction to the colon bacillus, Bacillus typhosus does not produce 
gas in any of the sugar media and produces acid in fewer of the 
sugars than coli; acid is produced in dextrose, levulose, galactose, 
mannite and dextrin, but not in lactose and saccharose and dul- 
cite, although in the latter acid may appear after several weeks. 

BIOLOGICAL PECULIARITIES WHICH SERVE TO DIFFERENTIATE THE 
TYPHOID BACILLUS FROM OTHER BACTERIA 

A very large number of methods and media have been devised 
for separating the colon-typhoid group of microorganisms from 
other bacteria, and still more for the purpose of rapid differentia- 
tion between typhoid, paratyphoid and other pathogenic members 
of the group and the colon bacillus. The latter, of course, are in 
particular designed to detect typhoid bacilli in the feces. These 
special methods are of great practical importance in the diagnosis 
of typhoid fever, in the detection of typhoid carriers and in the 
isolation of the typhoid bacillus from contaminated water, milk 
and food supplies. We shall discuss certain of these methods in 
more detail in those chapters which deal with the laboratory diag- 
nosis of typhoid, the carrier condition and the differential diagnosis 
of the paratyphoid infections. We are concerned here not so much 
with the methods employed in diagnostic work as with the media 
and reactions employed as throwing light on the biological char- 
acteristics of Bacillus typhosus. 

The in general superior motility of the typhoid bacillus has led 
to several methods designed to make use of this property in its 
separation from Bacillus coli. The semi-solid glucose gelatine- 
agar medium of Hiss serves in this way to differentiate colon from 
typhoid, since the latter on plating grow with peripheral, thread- 
like outgrowths into the media. 



THE TYPHOID BACILLUS 29 

Carnot and Weil-Hall6 J have made use of a "U" tube partially 
filled with sand through which the typhoid bacillus in a mixed 
culture will penetrate more rapidly into a bouillon medium stained 
with neutral red on the further side. The more rapid passage of 
Bacillus typhosus through filter paper and up into a fluid medium 
is employed by Wilman, who takes cultures at intervals and finds 
that the typhoid bacilli predominate at first even when more 
colon bacilli are present on the filter. 

Various methods have been employed to suppress or inhibit 
the growth of organisms other than those of the colon-typhoid 
group by employing substances which leave the latter relatively 
unaffected. The cruder methods such as heat and the addition 
of carbolic acid have long since been abandoned. Various media 
for this purpose have included iodine, as in Eisner's potato gelatine. 
Bile is commonly used, particularly in blood cultures, as offering 
a favorable medium for colon and typhoid but inhibiting cocci and 
diminishing the bactericidal property of the blood. Crystal violet 
is also used to accomplish the first of these purposes. 

Of even greater interest and importance are those chemicals 
which serve to differentiate between Bacillus coli and Bacillus 
typhosus by inhibiting the former. There are several important 
dye stuffs in this category, among which the most notable are 
malachite green, first employed by Loeffler and further perfected 
by Leuchs, and brilliant green employed in conjunction with 
picric acid by Conradi. 3 Malachite green has also been used in 
conjunction with bile. Both these substances inhibit the growth 
of colon bacilli and may be used either as a preliminary step in 
detecting typhoid bacilli or combined with other differential media. 
The value of both media has been repeatedly confirmed and de- 
tails in their preparation and use modified in many ways. The 
addition of caffein to suppress Bacillus coli was first suggested 
by Roth and by Gathens, and its value repeatedly re-asserted. 

An apparently very successful method of killing the colon 
bacilli and leaving typhoids and paratyphoids unaffected has 
recently been described by Bierast. 1 ' 2 He finds that petroleum 
ether will produce this effect if a preparation with the correct 
boiling point (about 50° C.) is employed. Bierast's results have 
been fully confirmed by Jaffe and by Hall. 1, 2 Actinic light has 
been employed by Dreyer, Walker and Gibson 1 for the same 
purpose. An exposure of agar plates seeded with mixed cultures 
to a graduated arc formed between silver electrods leads to sharp 
differentiation in appearance between the colon and typhoid colo- 
nies. 



30 TYPHOID FEVER 

Another group of diagnostic tests makes use of the greater fer- 
menting properties of the colon bacillus in sugars, particularly in 
lactose, which is unchanged by Bacillus typhosus. Capaldi and 
Proskauer prepared two media containing mannite and litmus, 
only one of which contained peptone. In the peptone-free medium 
Bacillus coli grows well and produces acid, Bacillus typhosus 
giving no change. In the peptone medium both grow but the 
typhoid bacillus alone produces acid. Several indicators have 
been employed in detecting acid formation. One of the best 
known media is the lactose-litmus-nutrose medium of Drigalski 
and Conradi. Typhoid colonies appear bluish, whereas colon 
colonies are red on this medium; the red color is probably due to 
lactic acid formation (Robinson and Rettger) and not to aldehydes, 
as has been claimed. This medium is frequently used in combina- 
tion with crystal violet to inhibit growth of other bacteria. Endo's 
lactose-basic fuchsin-sodium sulphite agar is even more favorably 
known. Colon colonies turn red and typhoid colonies are colorless 
or pinkish. Russell 2 renders the final differentiation of typhoid 
from alkali producers rapid and certain by transferring colorless 
colonies from the Endo medium to a double sugar medium pre- 
pared either in tubes with a solid bottom of glucose litmus agar, 
above which is slanted sterile lactose litmus agar, or by a mixture 
of the two sugars. The tube is inoculated by a combined stroke 
and stab culture which gives a blue background on the slant but 
a red glucose stab when the transplanted colony is the typhoid 
bacillus. 

Another indicator which has been used in conjunction with 
lactose is congo red (Schmitz, 1 Liebermann and Acel x ). Colon 
colonies are blue black and other bacteria red. 

Holt-Harris and Teague have employed an agar containing 
saccharose and lactose, to which is added as an indicator a mixture 
of yellowish eosin and methylin blue. The colon colonies on this 
medium are differentiated earlier than on the Endo plate, and 
have distinctive black centers. The typhoid colonies are trans- 
parent and remain so. This medium in our experience is a very 
good one and can be successfully employed even in the hands of 
beginners. 

Colon bacilli have a reducing action on certain media which is 
not shared by the typhoid bacillus. McConkey used an admixture 
of sodium glycocolate which is precipitated by the acid formed 
by Bacillus coli; he later added lactose and neutral red to this 
medium. Typhoid produces no change in either medium. Neutral 
red was suggested by Rothberger as a differential medium in stab 



THE TYPHOID BACILLUS 31 

cultures. Bacillus typhosus produces no change in the red, whereas 
Bacillus coli decolorizes and renders the medium fluorescent. If 
glucose be added, gas is formed by the colon organism. Botez 
finds that typhoid will not affect bouillon colored with methyl 
violet, whereas paratyphoid A decolorizes it partially and para- 
typhoid B and colon reduce it entirely. Levy and Vallery-Radot 
have employed media containing subacetate of lead and glucose 
for the differentiation of typhoid bacilli from the two paratyphoid 
organisms. It is found that the typhoid bacillus does not break 
up the medium and may or may not darken it. Paratyphoid A 
on stabbing produces fragmentation of the medium without chang- 
ing its color, whereas paratyphoid B both fragments and darkens 
it. 

THE TOXINS OF BACILLUS TYPHOSUS 

The typhoid bacillus produces symptoms and lesions in con- 
nection with the disease of which it is the cause, which are attri- 
butable to toxins rather than to its simple multiplication and 
parasitic existence in the body. The discovery of the soluble 
toxins of Bacillus diphtheriae and of Bacillus tetani about 1890 
gave rise to studies of other microorganisms from the same view- 
point. Pfeiffer's studies of the cholera vibrio in 1892 showed, 
however, that filtrates of bouillon cultures of this organism differ 
from diphtheria culture filtrates in being slightly, if at all toxic 
for guinea pigs. His further experiments, in conjunction with 
Kolle, showed, however, that the dead bodies of killed vibrios 
were fatal even in small doses; When normal guinea pigs are 
given an intraperitoneal injection of living cholera vibrios, they 
die in twelve to twenty-four hours with increasingly evident symp- 
toms, and cultures at autopsy show that the microorganisms 
have increased enormously throughout the body. In guinea pigs 
that have been immunized by repeated injections of small doses 
of killed cholera vibrios, a similar intraperitoneal injection of the 
dose of living vibrios which is fatal for the normal animal is fol- 
lowed by transitory acute symptoms of intoxication, rapid re- 
covery of the animal and disappearance of the cholera vibrio. 
Further investigation showed that both the acute intoxication 
and the recovery of the immunized animal is due to the same 
cause. Specific lysins are formed as a result of immunization 
which may be shown both in the animal body and in the test tube 
(Metehnikoff) to dissolve the vibrios, which not only destroys 
them but liberates their intracellular poisons or "endotoxins." 
It is evident, then, that under the conditions of immunization 



32 TYPHOID FEVER 

which Pfeiffer pursued, lytic bodies which destroy the vibrios 
were formed, but no antibodies capable of neutralizing their liber- 
ated endotoxins; he therefore defined endotoxins as bacterial 
products which differ from the soluble or exotoxins like those of 
Bacillus diphtheriae in residing only within the cell and in failing 
to give rise to antitoxins. 

Such intracellular poisons or endotoxins are obtainable from the 
bodies of most or perhaps all bacteria which do not give rise to 
the soluble toxins of the diphtheria-tetanus class. They may, 
moreover, be derived not only from pathogenic but from non- 
pathogenic bacteria. Toxic extracts of this sort have been ob- 
tained from the typhoid bacillus in several ways: by employing old 
macerated cultures (Sanarelli, 1892-1894); by killing with chloro- 
form and heating (Martin, 1898) ; by freezing with liquid air and 
grinding (MacFadyan and Rowland, 1903); by mixing with a 
solution of urea and freezing by methyl chloride (Balthazard) ; by 
drying and grinding with common salt (Besredka, 1 1905); by 
crushing under four hundred atmospheres in a Buchner press 
("Typhoplasmin" of Hahn, 1897); by autolysis (Conradi); or by 
splitting the microorganisms by alkali-alcohol (Vaughan, 1908). 
These extracts when injected into animals produce symptoms and 
lesions, which in some ways suggest relations to those of human 
typhoid fever, and which we shall consider in more detail presently. 
They cannot, however, be regarded as strictly specific in their 
action, as identical results may be produced with the extracts of 
other bacteria, for example, the colon bacillus. It may, however, 
be suggested that these experiments have not been carried out on 
anthropoid apes in whom alone the characteristic human syndrome 
has been produced with the living bacteria, and specificity could 
scarcely be expected from the toxic products in lower animals. 
The relation of this endotoxic product from the typhoid bacillus 
to the symptoms and lesions in typhoid fever we shall discuss in a 
later place; suffice it to say that the relation is by no means as 
simple a one as would appear, being complicated not only by the 
effect of a possible soluble toxin but also by the indefiniteness of 
our knowledge of the endotoxins themselves, and of the nature of 
bacterial anaphylatoxins. 

Preceding the work of Pfeiffer and Kolle, on which the concep- 
tion of endotoxins was founded, there had been observations that 
indicated that typhoid bacilli eliminate toxins into culture media 
during their growth. These observations date from the experi- 
ments of Brieger in 1883, thus antedating the actual growth of the 
typhoid bacillus in pure culture by a year. The observations, 



THE TYPHOID BACILLUS 33 

however, are rendered doubtful by the uncertainty as to whether 
pure cultures were actually obtained, by the complicating factor 
of possible toxicity of the culture medium itself, and by the in- 
definite nature of the poisons that were actually obtained. The 
later observations of Bandi, 1889, of Chantemesse, 1897, and of 
Rodet, 1898, seem to prove, however, that a true soluble toxin 
may be formed under certain conditions by Bacillus typhosus. 
These observations were to a considerable extent discounted during 
the following ten years when the endotoxin idea of Pfeiffer dom- 
inated conceptions as to the type of poisons that are actually 
formed by the majority of bacteria, in contradistinction to the few 
active toxin producers like diphtheria. Recent work, however, in 
the hands of Aronson, Meyer and Bergell, Kraus and Stenitzer, and 
Yamanouchi would seem to have proved conclusively that exo- 
toxins are produced by the typhoid bacillus if suitable conditions of 
medium and bacterial strain are chosen. These soluble toxins in no 
wise equal diphtheria or tetanus toxin in potency, but would seem 
to differ from them only in degree. Arima thinks that two differ- 
ent toxins are formed by Bacillus typhosus, an exo- and an endo- 
toxin, which he is able to differentiate on the basis of certain 
chemical reactions and the lesions produced experimentally in 
animals. The major results following the intravenous injection of 
the exotoxin in proper doses are a rise in temperature, paralysis, 
anorexia and marasmus; coagulation necrosis and waxy degenera- 
tion of the heart muscle and kidneys, swelling and hemorrhage of 
the adrenals, parenchymatous degeneration of the liver, and, 
finally, diarrhea. The endotoxin, on the other hand, produces a 
characteristic lesion in the intestine which suggests human ty- 
phoid, characterized by hemorrhages into Peyer's patches. These 
lesions are accompanied by fever, anorexia and marasmus. 

The production of soluble toxins by the typhoid bacillus is cer- 
tainly less easily demonstrated than the presence of toxic sub- 
stances lying within the bodies of the bacteria, and success in pro- 
ducing the former would seem to depend largely on the strain of 
bacillus employed and simple adjustments of the reaction of the 
culture medium. We cannot readily accept the sharp distinction 
which Arima would draw between the two toxins, which he has 
described, and it would seem to us more reasonable to assume that 
the difference between exotoxins and endotoxins lies, first, in the 
amount of toxin that is formed, and, secondly, in the ease with 
which the toxins are liberated from the body of any given bacteria 
rather than an essential difference in the toxic products them- 
selves. Variations in these two criteria would depend on the 



34 TYPHOID FEVER 

strain of culture employed and the suitableness of the medium in 
which it was grown. This lack of distinction between the two 
classes of toxins is further rendered probable by the fact that one of 
Pfeiffer's original criteria of endotoxins seems to have been dis- 
proved. Besredka has shown that the endotoxins of both cholera 
and typhoid can give rise to antibodies. These anti endotoxins 
are, to be sure, incapable of neutralizing any considerable number 
of toxin doses, but the point of interest here is that the typhoid 
antiendotoxin of Besredka will neutralize not only the endotoxin 
but also the exotoxin (Arima, Stenitzer). 

Both Castellani l and Levy and Levy have found that nitrates 
of sugar-free broth cultures of typhoid bacilli are hemolytic. 
These hemotoxins on injection into animals give rise to antibodies. 
There is no indication, however, that they play any particular 
role in human typhoid fever. 

MUTATIONS AND VARIATIONS IN BACILLUS TYPHOSUS 

The question of mutation in bacteria is one of the most interest- 
ing problems with which the science of bacteriology has to deal. 
In no particular instance is it more concretely of interest than in 
the case of the typhoid bacillus. Whereas Naegeli's original 
conception of bacteria was that they were essentially variable in 
appearance and function as well as in their properties of producing 
disease, the work of Cohn and Koch, on which our present day 
classification and ideas of specificity are based, depends essentially 
on the immutability of bacterial species. It is obvious that the one 
essential qualification in proving that a given microorganism is the 
cause of any given disease, is that it should be an entity sufficiently 
fixed so as to make its identification certain. The studies of 
recent years, however, employing more delicate methods of cul- 
tural and immunological differentiation, have tended to show that 
whereas a given bacterial species remains fixed in its principal 
characteristics, it may tend to fluctuate and to be divisible into 
groups in some of its less important functions. It has been shown, 
for example, that although the pneumococcus is still a recognizable 
entity as the cause of acute lobar pneumonia, it may be subdivided 
into several types on the basis of agglutination tests, which types 
are correlated with distinct differences in respect to relative 
pathogenicity. There is also a tendency to divide the gonococci, 
the streptococci, and the meningococci into similar groups. In 
the case of bacillary dysentery it is generally recognized that there 
are at least three or four well marked types of bacilli, any one of 



THE TYPHOID BACILLUS 35 

which may give rise to the characteristic disease. Not only do 
these different types occur in different cases in a given epidemic, 
but they may be shown to be present in a given case. It is evi- 
dent, then, that considerable variation may occur in a given 
species of bacteria without producing marked effect, except in 
degree, on the essential pathogenic properties of that micro- 
organism. The bacterium remains a recognizable and specific 
entity and the slight variations which we are beginning to recognize 
in members of a bacterial species may be produced experimentally 
only with the greatest difficulty or not at all. The Shiga and 
Flexner types of dysentery bacilli differ only in their response to 
immune sera and in the fermentation of certain sugars, and yet we 
cannot transform one variety into the other by any methods at 
present at our disposal. 

In a more extended way we may imagine that the typhoid and 
paratyphoid bacilli were originally derived from the colon bacillus, 
with which they may still be grouped in general characteristics. 
The typhoid and the paratyphoid bacilli produce definite and very 
similar human diseases, the similarity becoming more evident as 
we have learned more about the paratyphoid fevers, and yet they 
are fixed types in the sense that we differentiate entirely on the 
basis of the variations in these microorganisms between the 
paratyphoid and typhoid fevers. There are groups of bacteria 
intermediate between the closer paratyphoid organism (Bacillus 
paratyphosus A) and the typhoid bacillus, and these variations or 
mutations may remain more or less constant. There are further 
mutations among the organisms that may definitely be classified as 
typhoid bacilli. These mutations consist, first, in variations from 
the normal type in the appearance of the colonies or in the in- 
dividual organisms, and such forms may tend to remain constant 
in successive generations (Baerthelin). Other strains of typhoid 
bacilli isolated in epidemics which showed a predominance of the 
usual type have shown variations in respect to growth on the 
ordinary media. Jacobsen describes an organism to which he gives 
the name Bacillus typhus mutabile, which failed to grow on the 
Drigalski-Conradi medium, although other organisms in the same 
epidemic grew perfectly well. This mutant fermented mannite 
slowly and was only weakly agglutinated by an antityphoid serum; 
otherwise it grew like the regular strains of the organism. It 
finally became agglutinable and it could be shown that a slight 
change in the reaction of the medium led it to grow even shortly 
after its isolation. 

Most interesting, however, are the induced variations in typhoid 



36 TYPHOID FEVER 

bacilli that have been produced by several investigators. Twort 
by growth of an ordinary typhoid bacillus on two per cent lactose 
media for two years finally produced a strain which would ferment 
this sugar; this property remained constant even after passing 
the acquired strain through animals. Penfold studied this par- 
ticular strain as regards its acid formation on McConkey's lactose 
bile neutral red agar, and found that whereas a given colony when 
grown and seeded would produce equal numbers of red and of 
mixed pink and white colonies in the first generation, the subse- 
quent planting from a red colony would give ninety-five per cent 
of red colonies, and from a pink colony both pink, red and white 
colonies. When the organism was grown in bouillon that con- 
tained no lactose for five to twenty passages, it reverted to its 
original non-acid production, and all the colonies are white. Pen- 
fold was unable to produce similar mutants in a year from regular 
typhoid bacilli. He did, however, succeed in producing a strain 
that fermented dulcite in an increasingly shorter period of time. 
Mandelbaum has described a peculiar ("metatyphosus") form 
of organism which produces alkali in glycerine, although the or- 
dinary typhoid bacillus produces acid. He could not produce a 
similar mutant artificially, but was able to reduce the alkali form 
to the regular acid production in a number of generations. 

These variations in the metabolic activities of the typhoid 
bacillus, interesting as they are in proving the existence of mu- 
tants, are of less importance from the standpoint of the patho- 
genicity of the organism than are similar variations in the so- 
called antigenic properties of the bacillus. There is observational 
evidence which would seem to show that there is variation in the 
pathogenicity of different strains of the typhoid bacillus. It must 
be admitted that this evidence rests on no very secure foundation 
inasmuch as it cannot be experimentally verified, but it would 
seem evident, apart from the variation in resistance in individuals, 
that there is an actual variation in the severity of different epi- 
demics, and indeed in individual cases in a given epidemic, which 
seems to indicate that the infection in various cases may vary 
apart from the matter of dosage and the like. As we have stated, 
these matters are not subject to experimental investigation, al- 
though it has been the practice in what would seem to be a thought- 
less and arbitrary fashion to judge of the pathogenicity of a given 
bacterium isolated from a human case by injecting it into animals. 
This procedure, which has grown up as a sacred rite in many 
pathological laboratories, would seem devoid of any intelligent 
purpose. The mere fact that a given strain of microorganism may 



THE TYPHOID BACILLUS 37 

produce a more severe disease in rabbits than other similar strains of 
the same organism gives us no certainty that it will produce similar 
results in any other animal species. There is no reason, then, to 
draw any conclusions from the effect of a given bacterium isolated 
from a human case by observing its relative pathogenicity for 
animals. 

The matter of variations in pathogenicity is, however, of great 
importance when we consider the question of specific immuniza- 
tion, be it active or passive in type. There is ample evidence to 
show that the best type of active immunization or vaccination 
against a given microorganism is obtained by immunizing with 
the particular strain of microorganism against which protection 
is desired. This has been amply shown, particularly in the case 
of the streptococcus. We shall not enter at this point upon a 
discussion relative to the value of a single (monovalent) or of a 
polyvalent typhoid vaccine as giving protection against typhoid 
fever. That matter will be considered more particularly under 
the discussion of protective vaccination against this disease. We 
do wish, however, to point out not only that variations occur in 
the antigenic properties of typhoid bacilli as they are isolated, 
but that they may be artificially induced in them. It is first of all 
well recognized that recently isolated strains of typhoid bacilli 
are not infrequently difficult to recognize on account of their 
failure to produce the characteristic reaction to an antityphoid 
diagnostic serum. This relative inagglutinability corresponds, 
we believe, to a growth in the body on a different type of medium 
than the one ordinarily used to grow bacteria outside the body, 
and the inagglutinability may be induced, as Gay and Claypole 
have shown, by growing the typhoid bacillus on a blood medium. 
Typhoid bacilli vary in their property of producing soluble toxins, 
according to Kraus and Stenitzer. An artificial resistance of 
typhoid bacilli may be produced not only to chemical substances, 
as indicated by the references we have given on the variation in 
fermenting properties, and further work which has shown that the 
organisms may be made relatively resistant to a substance such 
as quinine by successive growth in this medium (Haendel and 
Baerthlein), but also to serum. Braun and Feiler, and Neufeld 
and Lindermann have both shown that growing typhoid bacilli 
in normal or in immune serum may make them relatively resistant 
to destruction by the serum in question. The general experience 
that the presence of fixation antibodies in the serum of typhoid 
cases can only be detected to best advantage by the use of a polyv- 
alent antigen is best indication that variations occur in the in- 



38 TYPHOID FEVER 

dividual organisms that may cause the infection in any given 
case. 

It has recently become evident that not only may variations in 
the antigenic properties of typhoid bacilli occur and be artificially 
induced, but that such variations may to some extent serve to 
classify the strains into groups. Hooker in a very careful study 
of the antigenic properties of strains of typhoid bacilli has found 
that consistent differences may be detected by means of very 
delicately adjusted alexin fixation reactions or by means of ag- 
glutinin absorption experiments. He was able to divide the ty- 
phoid bacilli which he studied into three groups of this sort. His 
observations indicate not so much that the groups vary remark- 
ably among themselves when recently isolated, but rather that 
old cultures of the organisms tend to lose certain antigenic proper- 
ties, and his facts are applicable perhaps rather to the type of 
bacillus (a recent strain) which should be used in preparing vaccine 
for protection. There is, however, evidence at least from his 
agglutinin absorption experiments of distinct antigenic differences 
among recently isolated strains. Weiss has independently corrob- 
orated and extended these observations of Hooker. This writer 
found that he could divide the strains of typhoid bacilli which he 
studied into several groups, not only on the basis of agglutinin 
absorption experiments, but also by their ability to ferment xylose. 



CHAPTER IV 

THE MODES OF INFECTION IN TYPHOID FEVER 

It will be recalled that one of the criteria by which Gerhardt 
and others were enabled finally to differentiate typhus from ty- 
phoid fever was the high degree of contagiousness, as they called 
it, or as we should now better say transmissibility, of the former 
and the supposed non-contagiousness of the latter. We find that 
the physicians of the early nineteenth century were practically 
unanimous in regarding typhoid fever as entirely non-contagious, 
but, as we shall see, this belief gradually changed with the sub- 
sequent observations which we shall endeavor here to trace. The 
French physicians, Chomel, Bretonneau, Louis and others, were 
the first accurately to describe typhoid fever on the basis of its 
characteristic lesions, although they did not have sufficient ex- 
perience with typhus to be able to differentiate it from this latter 
disease. 

TRANSMISSIBILITY OF TYPHOID FEVER AND GENERAL CONCEPTIONS 
OF ITS MODES OF INFECTION 

According to Bartlett, Nathan Smith in 1824 was the first to 
refer to typhoid as transmissible from one individual to another. 
Inasmuch as the disease was not at that time clearly separated 
from typhus, no particular significance can be attached to this 
observation. It was undoubtedly Leuret in 1828 who proved 
that a series of cases of typhoid in Nancy, which were anatomically 
verified, could be traced to a stranger suffering with the disease 
who came to the city. In the following year (1829) Bretonneau 
gave further evidence on the transmissibility of the disease, which 
he was able to follow owing to the fact that the cases he observed 
occurred in the country, where for reasons that will later be men- 
tioned the course of epidemics is more readily followed. In 1834, 
Gendron proved conclusively that in several instances a number 
of cases of typhoid occurred in a series following the introduction 
of an imported case, and made definite statements as to the 
probable method of its transmission. He concluded that the 
majority of cases arise through direct or indirect contact of healthy 
individuals with one sick of the disease, either through living in 

39 



40 TYPHOID FEVER 

the same atmosphere or indirectly by means of the clothing or 
utensils that have been handled by the patient. He further stated 
that epidemics of typhoid are the result and not the cause of the 
contagion. Contagion would apparently depend on the direct- 
ness of communication between the individuals affected, and 
bears no relation to the sanitation of the locality in which the 
disease arises. Gendron, however, ingeniously points out that 
typhoid fever is more contagious at certain stages of its evolution 
and may be transmitted even by convalescents. 

Dupre" was apparently the first (1823) to mention the impor- 
tance of water as a means of transmission of the disease (Brouardel 
and Thoinot). Austin Flint in 1843 records a memorable epidemic 
which occurred in North Boston, New York, in which a series of 
cases could be traced directly to those who had drunk of the water 
at an inn in which a traveler had fallen ill of typhoid. 

The evidence in favor of the contagiousness of typhoid was 
summarized by Piedvache in 1849, who defined contagion in a 
manner that is particularly acceptable for typhoid fever in the 
following words: "Toute transmission de la maladie d'un individu 
malade a un individu sain quel que soit le mode suivant lequel 
elle s'opere." This author regards typhoid as contagious in at 
least the majority of cases, in which viewpoint he had been pre- 
ceded by Louis in the second edition of his well known book on 
the disease. 

The other important link in the chain of evidence which proved 
the transmission of typhoid fever from one individual to another, 
was the recognition that the "contagion" or vehicle of infection 
was from the sick to the healthy by means of the excreta. This 
was apparently first clearly stated by Canstatt in 1847. Riecke 
in 1850 apparently connected the two significant factors of excreta 
and water by showing that a number of epidemics could be di- 
rectly traced to the ingestion of drinking water that had been 
polluted with sewage. 

It remained, however, for William Budd to furnish complete 
and sequential proof of the successive steps in the usual mode of 
transmission of typhoid. In two remarkable articles published 
in the Lancet in November and December, 1856, 3, 4 he outlines 
his conception of the nature, mode of spreading and prevention 
of typhoid, which he further amplified in his book published in 
1873. 2 Since the conception of this author represents the essential 
framework on which our present conception of the mode of trans- 
mission of this disease rests, it will be worth while to give his major 
conclusions in some detail. According to Budd, the living con- 



MODES OF INFECTION IN TYPHOID FEVER 41 

tagion of typhoid fever inhabits the human body primarily, in 
which place alone it finds conditions suitable for its development. 
The disease which this contagion produces is transmitted more 
or less directly from one individual to another by means of the 
excretions and effluvia from the first affected person. The prin- 
cipal excretion responsible for the transmission is the feces, and 
sewage is to be regarded, in so far as the transmission of the disease 
is concerned, as simply a continuation of the intestinal canal. 
Ordinary sewage, uncontaminated by typhoid excreta, is not 
capable of causing typhoid fever, however much it may con- 
taminate the water which is the usual vehicle by which it reaches 
the second person. Budd attributed his success in tracing the 
course of several epidemics to the fact that his observations were 
made in the country where sanitation is less perfect than in cities. 
Excreta were deposited upon the ground and could then be shown 
in a number of cases to be washed by rain or in other ways to reach 
water supplies, which gave rise to other cases. In other instances 
it was shown that the disease was transmitted from one to an- 
other by the hands coming in contact either with the sick indi- 
vidual or with fomites which had been soiled with the excreta 
from such an individual. Budd further mentions definite in- 
stances in which people were apparently able to give rise to epi- 
demics even though they themselves had for some time been 
without fever and apparently restored to health, thus forestalling 
the important conception of recovered carriers which was not 
elaborated until many years later. He further points out that 
failure to succeed in tracing any case or epidemic to a preceding 
case of typhoid is a fallacious means of proving that such trans- 
mission has not in reality taken place. The English author was 
by no means satisfied with explaining typhoid epidemics, but took 
vigorous and successful means in preventing their further spread 
and recurrence by laying down thoroughly practical and successful 
methods of disinfection, which are as applicable today as when 
they were proposed. 

Before passing to more modern and more detailed explanations 
of the entire question of typhoid transmission, we may mention 
two theories which were developed in the middle of the nineteenth 
century, although they in reality added little to Budd's theory, 
and indeed in some respects serve to obscure it. As we have al- 
ready stated in the first chapter, Murchison contributed addi- 
tional facts which prove the communicability of typhoid and its 
transmission through the feces, although his explanation was 
marred by the assumption that certain fermentative changes in 



42 TYPHOID FEVER 

the feces of a typhoid case were necessary before the contagion 
was again capable of producing the disease. He further made the 
serious error of assuming that spontaneous generation of the 
disease was possible in sewage which had been uncontaminated 
by typhoid excreta. The ground-water theory of Buhl and Petten- 
koffer is interesting only so far as the importance of water as a 
vehicle of transmission is indicated, but is wholly incorrect in 
again assuming the spontaneous origin of the disease. 

The preceding sketch of the development of knowledge concern- 
ing the mode of transmission of typhoid fever, extending to the 
middle of the nineteenth century, may, when supplemented by 
the data introduced by bacteriology, be regarded as comprising 
the essential facts in our present day knowledge. All subsequent 
information, extended and elaborate as it is, has not supplanted 
the explanation of Budd, and has for practical purposes added 
little to it. The first fact of importance is that every case of 
typhoid fever arises directly or indirectly from some previous 
case. The first link in the chain which connects one case with 
another lies in the dejecta and objects that have been in contact 
with the first patient. Contaminated water is the most frequent 
vehicle by which the infection actually reaches the second in- 
dividual. If all dejecta from the first case were destroyed and all 
direct contact were prevented or neutralized by cleanliness, ty- 
phoid fever would cease to exist. The disinfection of the feces is, 
as we now recognize and as Budd emphasized, the most logical 
and vulnerable point at which to interrupt this self-perpetuating 
malady. 

SOURCES OF INFECTION FROM THE TYPHOID PATIENT 

An exposition of the disease entity which we are considering 
may begin at any point in the continuous chain which stretches 
through one case of typhoid fever to the next victim. We have 
chosen to begin with a consideration of the parasitic essential 
agent of the disease, the typhoid bacillus. We have examined 
this microorganism as it may be studied under artificial condi- 
tions outside the human body. In the present chapter we are 
investigating the natural but still less favorable conditions under 
which it occurs "at large," and shall endeavor to trace it to its 
normal habitat in the body of man. In following the course of 
the typhoid bacillus from one host to another we may begin by a 
brief summary of the conditions under which it is present in the 
body, and its method of leaving it, forestalling in a way the full 
consideration of these phases which we take up later. 



MODES OF INFECTION IN TYPHOID FEVER 43 

Any case of typhoid fever may serve as an immediate source of 
infection for healthy individuals, and all typhoid cases are in the 
last analysis derived from previous cases. Each individual case 
varies as a potential source for the further propagation of the 
disease in a degree which varies, depending on the number and 
virulence of bacteria eliminated. Each particular case, moreover, 
varies at different stages in its development in the number of 
bacteria excreted. A typhoid case may excrete bacteria at any 
time during its course, not only during the stage of active mani- 
festations of the disease, but before and after this period. The 
course of the disease, moreover, includes the incubation period, 
during which the patient is apparently perfectly well, and al- 
though at this stage the number of bacteria is probably less, the 
actual dangerousness of the individual as a source of infection is 
probably greater, owing to the fact that no suspicion as yet at- 
taches to him. This same absence of diagnosis renders infection 
quite common from cases in the first week of the fever. It has 
been estimated, for example, by Conradi that fifty-eight per cent 
of the cases in an epidemic which arose from a certain case were 
caused by the excretions during the first week. From the third 
week on typhoid bacilli may be found with greater regularity in 
the feces, in some seventy-five to eighty per cent of all cases. The 
actual detection of the organism, naturally, falls short of its ac- 
tual occurrence in the feces, and from what we know of the course 
of the disease, we may assume that it is always present. Atypical 
cases of typhoid are particularly dangerous from the standpoint 
of hygiene, owing to the fact that their real condition is not appre- 
ciated. Among these may be mentioned the ambulatory and 
mild cases of typhoid, and particularly typhoid as it occurs in 
children, where it is frequently not correctly diagnosed. 

Typhoid carriers are the source of many subsequent cases, and 
the proof of the existence of these individuals may be regarded as 
one of the triumphs of preventive medicine. The carrier, like the 
case of typhoid during the incubation period, is a great danger 
because unsuspected. Large epidemics, particularly food epi- 
demics, may be directly referable to carriers, and they constitute 
a very important source of infection, although the estimates 
which are given as to the total percentage of cases caused by car- 
riers vary considerably and depend, of course, on the individual 
experience of the author. Percentages ranging all the way from 
two to thirty have thus been attributed to carriers. Typhoid 
carriers may be divided into three categories: carriers in recovered 
typhoid cases, which are subdivided into temporary and per- 



44 TYPHOID FEVER 

manent; and the healthy carriers. Whereas the typhoid bacilli 
disappear from the feces in the majority of cases during con- 
valescence, they persist for a few days or weeks in four or five per 
cent of recoveries. In two per cent they persist for two or three 
months, and in something like one per cent they persist beyond this 
period. The latter individuals are the true permanent carriers. 
Healthy carriers are those individuals who have never, so far as is 
known, suffered from frank typhoid fever, but who nevertheless 
harbor the bacilli in their intestines. We shall later give reasons 
for assuming that these cases must in reality have passed through 
a mild attack of the disease, since it is probable that the excreted 
organisms come from the gall bladder after having passed through 
the body rather than from simple multiplication in the intestine. 
Carriers serve as sources of infection, particularly in those cases 
that are infected through contact, and most frequently in those 
in which the contact is indirect, as in the preparation and con- 
tamination of food. The percentage of women among the carriers 
is higher than men. 

As we have already described, the means by which the typhoid 
bacillus leaves the body of the original case is primarily through 
the feces. As has been stated, the typhoid bacillus can actually be 
found in eighty per cent of cases in the feces, and is undoubtedly 
present in every case and probably in very large numbers. It 
tends, however, to disappear somewhat rapidly after excretion from 
the body in manners which we shall presently describe. The urine 
is the next most frequent route by which typhoid bacilli leave the 
body. Twenty-five per cent of all cases give positive cultures from 
the urine and most frequently during the third week of the disease. 
The bacilli are not only present during the disease, but, as in the 
case of the feces, may be present after recovery for varying and 
considerable lengths of time. It has been estimated that seven 
per cent of all permanent carriers are urinary and the majority of 
these are women. The typhoid bacillus occurs in the urine, par- 
ticularly when it is alkaline. The danger of indiscriminate scatter- 
ing of the bacilli has been pointed out to be somewhat greater 
from the urine than from the feces. 

In addition to the feces and urine, which represent the major 
sources of the typhoid bacillus in the human body, there may be 
mentioned certain other excreta which at times not only contain 
typhoid bacilli but also may at least be assumed to give rise to 
further cases. Among them there may be mentioned the sputum, 
which, during the occurrence of typhoid ulcers in the throat or of 
typhoid bronchial pneumonia, has been shown to contain numbers 



MODES OF INFECTION IN TYPHOID FEVER 45 

and often pure cultures of the specific bacillus. The vomitus during 
the early stage of the disease, particularly when bile-stained, con- 
tains typhoid bacilli. Certain of the localized complications of 
typhoid fever which occur not infrequently during or after con- 
valescence, are due to the typhoid bacillus, which may be in pure 
culture or mixed with other organisms. Thus, otitis media and 
necrosis of the bone may occur for very long periods after the 
disease. Netter (Vincent and Muratet) has described a form of 
vulvitis in children produced by the typhoid bacillus which might 
readily serve as a source of infection. 

THE TYPHOID BACILLUS AT LARGE 

Typhoid bacilli under ordinary circumstances begin to diminish 
immediately on their discharge from the body of their host, and 
this fact serves as one of the safeguards in the distribution of the 
disease. Each successive link in the chain which connects the 
first typhoid case with the second would in general tend to diminish 
the danger of infection owing to this fact that the microorganisms 
are living in unfavorable surroundings. We shall discuss the 
conditions in each of these stages of transmission as we reach 
them, and may content ourselves here with certain observations 
as to the life of the typhoid bacillus in the feces. It is probable 
that the microorganisms in feces do not survive for any con- 
siderable period of time. Park has shown that the majority of 
organisms in his experiments survive only a few hours, although 
in some specimens they were present as long as fifteen days. 
It is probable that the reaction of the stools is of considerable 
importance in determining the longevity of the typhoid bacillus. 
Rosenau estimates that under ordinary conditions the organism 
survives for from two to seven days. Vincent and Muratet cite 
experiments which indicate that the duration is considerably 
longer, from twenty-five to thirty days, and Levy and Kayser 
found organisms in a cemented privy vault five months after their 
excretion. A number of factors intervene in determining the life 
of the typhoid bacillus, both in the feces and in other media, with 
which they become contaminated. Certain requisites are neces- 
sary for the life of the bacillus itself, the principal ones being food, 
the exact composition of which is not certain, moisture, and 
warmth. Among the harmful influences that tend to destroy the 
typhoid bacillus are sunlight and temperatures too far above or 
below that of the human body. Other factors which contribute in 
the destruction of the bacillus are antagonistic bacteria and, when 



46 TYPHOID FEVER 

the feces are mixed with the general sewage, the absence of oxygen. 
It seems certain in general that the greater the general pollution, 
apart from the typhoid bacillus, the less the opportunity of the 
latter to grow. It seems fairly well demonstrated that the typhoid 
bacillus will live longer in clean water than in sewage. The ty- 
phoid bacillus may, however, persist even in the effluent from 
septic tanks. 

ROUTES FOLLOWED BY THE TYPHOID BACILLUS FROM ONE INDIVID- 
UAL TO ANOTHER 

The typhoid bacillus having left the body of the typhoid pa- 
tient or carrier with the feces and urine, or perhaps in some in- 
stances with other excreta, may follow a more or less direct route 
in reaching the mouth and gastro-intestinal tract of its next victim. 
The various routes of transmission have been followed with vary- 
ing accuracy and certainty in innumerable cases and epidemics, 
and increasing unanimity has been reached as to the more impor- 
tant ones. We might follow these routes and the vehicles of 
infection that constitute them in the order of their importance, 
but since estimates as to relative importance differ and the stages 
in the routes vary in number, it may be clearer to discuss the 
known or suspected paths in the order of their complexity. 

Contact Infections in Typhoid 

Routes 1-5 

In recent years more and more emphasis has been laid on cases 
of typhoid due to contact, and contact, again, has been found to be 
direct or indirect. Accepting the excreta, in particular the feces, 
as the extra-corporeal source of typhoid bacilli, the contact cases 
obtain their bacilli by the following graphically expressed routes, 
the significance of which will be further elaborated. 

1. Fingers or utensils to mouth. 

This is the route of direct contact. 

2. Fingers, to food, to mouth. 

3. Fomites, fingers, food, to mouth. 
Jf. Flies, food, to mouth. 

5. Fomites, flies, food, to mouth. 
These four latter routes are those which constitute the means of 
indirect contact cases. 

In the group of direct contact cases fall particularly those 
individuals who have to do with the care of the sick. Nurses and 



MODES OF INFECTION IN TYPHOID FEVER 47 

physicians have long been recognized to be very much more liable 
to contract typhoid fever than ordinary individuals. The reason 
for this greater susceptibility is evident. Their fingers come in 
contact with the bodies of typhoid patients and with their excreta, 
and in instances where rigorous cleanliness is not followed, these 
contaminated fingers readily transmit infection to the mouth. 
Physicians and nurses, moreover, are not only themselves open to 
infection through this channel, but other non-typhoidal patients 
whom they may handle in practice or in the hospital may be in- 
fected in the same manner. This latter possibility accounts in 
part for the spread of typhoid fever, which may occur from bed 
to bed in hospital wards. Fingers, however, are not the only 
means of direct contact infection of this type. Any object that 
has come in intimate contact with the patient may serve as a di- 
rect method of transmitting infection, particularly those instru- 
ments that have been placed in the mouth, such as thermometers, 
cups, spoons and glasses, which, if utilized by another individual 
without careful cleaning, may transmit the disease. The eating of 
food remnants that have been left by typhoid cases, particularly 
as it occurs among children in the home, may serve as a means of 
transmission. Kissing is another possibility that has been men- 
tioned as a similar channel. 

The direct contact cases are said to be peculiarly severe, which 
may be attributed to the unaltered virulence in the microorganism, 
which suffers no deterioration outside of the body. Cases con- 
tracted in this manner are due peculiarly to lack of cleanliness of 
a grade that should be avoidable. Direct infection may also 
occur from carriers, although this is not so likely a route in typhoid 
fever as it is in other infectious diseases which also have carriers, 
as diphtheria, cerebrospinal meningitis and poliomyelitis. In 
these latter infections the diffusion of the infective agent is more 
indiscriminate and its nature is less well recognized. 

The first mode of indirect contact transmission, as represented 
by the formula — fingers, food, mouth — is characteristic of those 
cases which emanate from carriers. In the first place, as has been 
mentioned, women predominate as typhoid carriers, and they 
are, of course, the individuals particularly concerned in the prep- 
aration of food, and it is through food stuffs prepared by such 
individuals that the disease may be transmitted in some instances 
to large numbers. Food, moreover, is not only a relatively direct 
route to the mouth of the individual, offering little harmful in- 
fluence in the external life of the typhoid bacillus, but may ac- 
tually serve as a culture medium for the microorganism. A strik- 



48 TYPHOID FEVER 

ing instance of this mode of transfer which brings out the latter 
possibility has been reported by Sawyer l in an epidemic of ty- 
phoid which occurred in Hanford, California, where a carrier pre- 
pared a dish of spaghetti which was allowed to stand over night 
and then browned on the following day and served to a large 
number of people at a church dinner, of whom ninety-three came 
down with the disease. Subsequent laboratory experiments 
showed that spaghetti prepared in this manner allowed an enor- 
mous multiplication of the microorganisms, which were not sub- 
sequently killed by the heat necessary to brown the dish. The 
handling of milk by carriers is another mode of transmission of 
this sort, which frequently gives rise to epidemics of considerable 
size, following the routes of distribution of milk. Localized water 
supplies may also be infected, as was the case in an epidemic on 
shipboard likewise reported by Sawyer, 2 in which it was found 
that a carrier had infected the water butt, from which other mem- 
bers of the crew drank, by dipping his hand into the water to fill 
his cup. 

Personal infection occurs in this indirect contact manner as 
well as the infection of other individuals in those cases where 
people who have handled typhoid fever patients or their excreta 
may contaminate their own food through a failure to wash the 
hands. We may here also for convenience include the majority 
of cases of laboratory infection from cultures of typhoid bacilli 
and also from the organs of those dead of the disease. The route 
in these cases may, of course, be simply direct, as in the first type 
of contact infection that has been studied, or may be indirect 
through soiled fingers to the food of the individual who becomes 
infected. 

The third rubric that we have given includes another link in 
the sequential chain which serves to transmit typhoid bacilli from 
feces to the mouth. It differs from the last group in introducing 
fomites, which have become infected with feces or other excreta 
from typhoid cases. The cases of typhoid which occur among 
washerwomen are an example of this type of infection. When 
these women are called upon to wash the unsterilized linen from 
typhoid cases, they may readily infect their hands and subse- 
quently their food and come down with the disease. Hospital 
cases of typhoid are also at times traceable to such a source through 
contaminated linen or towels that have been used on typhoid pa- 
tients. Armies are particularly prone to indirect contact infection 
of this type. The danger of abandoned camps has been repeatedly 
emphasized by military observers (Vincent and Muratet). A 



MODES OF INFECTION IN TYPHOID FEVER 49 

recent report of Uhlenhuth, Olbrich, and Messerschmidt would 
attribute the typhoid fever that occurred in German troops in 
France in the great world war to the contact infection from con- 
taminated localities. Army blankets have likewise been shown to 
transmit typhoid several months after being used on a case of 
the disease, and clothing used by soldiers, either dead or recovered 
from typhoid fever, may also serve as a mode of transmission. 
Firth and Horrocks (Whipple, p. 68) have shown that typhoid 
bacilli will survive on khaki or serge cloth for two or three months. 
Perhaps the greatest danger, not only in camps, but also in civil 
cases, particularly in the country, is the danger of contaminating 
the shoes by walking on ground over which typhoid excreta have 
been scattered, and subsequently transmitting the bacilli by the 
fingers from the shoes to the mouth. The importance of this type 
of contact infection in armies may be gathered from the estimate 
that 62.8 per cent of all the 20,000 cases which occurred in the 
Spanish-American War were due to infection of this sort, and ob- 
servations in the Boer War indicate that the percentage was prob- 
ably as high there also. 

In the fourth and fifth types of contact transmission an animate 
agent of a new sort is introduced. Sedgewick 2 was perhaps the 
first (1892) to suggest that flies are of importance in the spread 
of typhoid fever. The report on the epidemics of typhoid in the 
Spanish-American War by Reed, Vaughan and Shakespeare made 
it very evident that the swarms of flies which had free access to 
the uncovered latrines, and subsequently to the food eaten by the 
soldiers afforded a very significant means by which at least some of 
the cases were transmitted, although the majority of them could 
be attributed, as has been stated, to a type of contact infection 
that has been just discussed. These observations, whereas sig- 
nificant, are at best only circumstantial, and it remained for the 
work of Hamilton to prove conclusively that the ordinary house 
fly, musca domestica, in houses in which cases of typhoid fever 
exist could be shown to contain typhoid bacilli. These observa- 
tions have subsequently been confirmed by Ficker and by Klein. 
The failure of certain authors to confirm these observations should 
not be taken as militating against them, since this is one of the 
instances where a positive finding in competent hands is of far 
greater significance than many negative results. Epidemiological 
studies in many places have only confirmed the importance of 
flies in the spread of typhoid. Epidemics of army typhoid in 
South Africa and in India (Chapin) have been shown to have a 
direct relation to the number of flies that were present, and Odium 



50 TYPHOID FEVER 

(Vincent and Muratet) found that the systematic killing and 
guarding against flies caused a rapid cessation of an epidemic in 
India in the midst of a typhoid season, which again returned when 
such precautions were omitted. Hill has stated that typhoid 
fever occurring in the lumber camps of Minnesota likewise seems 
to bear a direct relation to the number of flies that are present and 
allowed to have access to unprotected water closets (Chapin). 

Flies may transmit the typhoid bacillus either by the mechanical 
sticking of the organisms to the exterior of the insect or by the 
passage of the bacillus through the gastro-intestinal tract and its 
elimination in the feces. It has been claimed (Whipple) that 
under artificial conditions flies may retain the typhoid bacillus 
in their bodies for twenty-three days. The possibility of other 
insects serving as transmitters of typhoid is rendered possible by 
the almost incredible experiments of Dutton, who allowed bed 
bugs to bite a typhoid fever case and subsequently produced the 
disease in healthy individuals by the bite of these same insects. 

Water Infections in Typhoid 
Routes 6, 7, 8 

6. Water to Mouth. — We have already seen that contaminated 
water was the first recognized and apparently the most significant 
vehicle of typhoid infection. Reduction in typhoid morbidity 
during recent years has been largely at the expense of the water- 
borne cases, owing to improvement in water supplies, and yet 
water still remains the most important single channel by which 
the typhoid bacillus reaches the human body. Estimates vary 
as to the total percentage of typhoid cases that are referable to 
water infection; somewhere from ten to forty per cent in the 
opinion of different authors. The importance of water in pro- 
ducing epidemics of typhoid is even more marked than in the pro- 
duction of individual cases. According to Spitta, Schuder found 
that of 640 typhoid epidemics seventy-two per cent were due to 
water, and Schegendahl found that of 682 cases about thirty- 
three per cent were water-borne. Not only is water an important 
channel in conveying typhoid fever, but, conversely, typhoid is 
the most important water-borne disease. 

Typhoid bacilli in excreta may reach a water supply in several 
ways. Feces may be thrown directly into the water; excreta may 
be deposited on the surface of the ground and washed therefrom 
into a water supply, particularly into wells by rains; or the overflow 
from privies in heavy rains may likewise be washed into drinking 



MODES OF INFECTION IN TYPHOID FEVER 51 

water. Perhaps the most common method of water contamination 
from sewage is by means of surface water or by subterranean 
percolation of the sewage, which may extend for very considerable 
distances, particularly if the soil is chalky in nature. An accidental 
connection between sewer pipes and water pipes may occur, or 
regurgitation of sewage may take place in faulty valves of a water 
supply. The dumping of mud near the intakes in supplies of lake 
water has at times given rise to epidemics. 

The typhoid bacillus survives in water for varying periods of 
time, which increase directly with the purity of the water. In 
sterile water the organism may survive for as long as three and 
one-half months, although it is not to be supposed that any marked 
multiplication of the organisms takes place, as water cannot be 
regarded as a culture medium for the microorganism. As the 
pollution of the water increases, the survival of the typhoid bacillus 
is shortened. In river water it has been estimated by Park and 
Williams to last for from two to seven days. It survives longer in 
water that is still than in water that is in motion, which is the 
reason why running streams have a certain though very limited 
tendency to purify themselves. Warm water is more favorable for 
the resistance of the typhoid bacillus than is very cold water. 
Although the majority of typhoid bacilli disappear from water in a 
very short period of time, the resistant minority, which may be 
sufficient to produce infection, may survive for several weeks or 
months. Exposure of shallow water to the rays of direct sunlight 
is, of course, an inhibiting factor on the resistance of bacteria. 

The proof that cases of typhoid fever are due to water infection 
is of two general sorts. In the first place, typhoid bacilli have 
been found in the water which gives rise to epidemics. This 
isolation of the typhoid bacillus from naturally contaminated 
waters is, however, extremely difficult, and has actually been 
accomplished only seven or eight times. Even in those cases 
where the organism is found, it is not always possible to prove 
that it was present at the time the cases under investigation were 
infected. The suspicion of any given source of water usually rests 
upon presumptive tests through demonstration of sewage pollution 
by the presence of colon-like bacilli in such materials. By far the 
more usual and satisfactory method of proving the water origin of 
typhoid lies in the epidemiological evidence which in certain in- 
stances at least is extremely convincing. In the most convincing 
cases it may be definitely proven that typhoid excreta have 
reached the water supply, a demonstration which is directly con- 
nected in point of time and distribution of the water with the 



52 TYPHOID FEVER 

outbreak of a group of cases. Less convincing evidence is present 
in those cases in which a water supply, known to be contaminated 
or probably contaminated, determines in its distribution a series 
of typhoid cases which disappear when the water supply is changed. 
The cases of typhoid occurring after water contamination may be 
grouped under two general headings. A single accidental con- 
tamination, as, for instance, when excreta are thrown into the 
water, may be followed by an explosive and acute epidemic of 
typhoid, which subsides rapidly; or in the second case a con- 
tinuous endemo-epidemic form of typhoid may exist in which 
sporadic cases are interrupted by acute exacerbation in the form 
of larger or smaller epidemics. It has also been shown by Winslow 
that water-borne epidemics of typhoid are frequently followed by a 
number of contact cases, to which form of spread he has given the 
name of "prosedemic." 

The general characteristics of cases attributable to water con- 
tamination, then, are that they are frequently in epidemic form, 
and that such epidemics begin in an explosive manner and are 
localized to the areas supplied by the water under consideration. 
Water-borne typhoid epidemics occur characteristically in cities, 
although they may readily occur through well contaminations and 
in more localized form in country towns. Another characteristic 
which frequently draws attention to the water supply as the cause 
of an epidemic of typhoid is its occurrence out of the regular 
typhoid season. Any considerable increase in cases in winter 
months, for example, would at least lead one to suspect a source of 
this kind. 

Contaminated water produces typhoid, at least as we are con- 
sidering it at this point, by entrance directly into the gastro- 
intestinal tract. It is, of course, primarily through drinking that 
such cases occur, although brushing the teeth in contaminated 
water may produce the disease. Dilution of contaminated water 
in the ordinary manner by wine, a device sometimes adopted with 
the idea of sterilizing the water, has been shown experimentally to 
be ineffective in killing the typhoid bacillus. It has been shown 
that soda water and other soft drinks will retain living typhoid 
bacilli for considerable periods of time, although such beverages are 
probably rarely or never contaminated under natural conditions, 
and are of little significance in the actual spread of the disease. 

A few outbreaks of typhoid fever have been traced to ice con- 
taminated by the typhoid bacillus. Cases due to this cause must 
be extremely rare, as the freezing of water tends to purify it, and 
those instances that are definitely known to be due to this source 






MODES OF INFECTION IN TYPHOID FEVER 53 

have been shown to be due to gross contamination on the surface 
of natural ice ponds or to careless handling by unclean hands. 
Park and Williams have shown that the great majority of typhoid 
bacilli of various strains, when artificially frozen, are destroyed in 
one or two weeks; there remain, however, a resistant minority of 
something like one-tenth of one per cent of the organisms which 
survive as long as five weeks. The best evidence that ice is an 
infrequent cause of typhoid fever is that there is no marked in- 
crease in the morbidity rate in large cities during the early months 
of summer when ice is freely used. 

7. Water, Food, Mouth. — Infections following this course are 
simply by one degree more complex than those that have been 
considered under the last heading. Contaminated water may 
transmit the typhoid bacillus either through admixture or through 
its use for cleaning receptacles to various types of food, which in 
turn become sources of infection. Among the most notorious in- 
fections of this type are those which occur from shell fish. Oysters 
in particular have been for many years suspected of being a possi- 
ble source of typhoid infection. It remained, however, for Conn in 
1894 to demonstrate that an epidemic of typhoid which occurred 
among the students in Wesleyan University could be directly 
traced to oysters consumed at a banquet, which had been fattened 
over a period of several days near the outlet of a sewer. It has 
been a common custom to fatten or bloat oysters by shifting them 
after removal from their original beds to a place where they are 
exposed to a fresh water stream. Such streams when near large 
centers of population are, of course, grossly contaminated with 
sewage. The epidemic described by Conn has been several times 
paralleled not only in this country but in France (Chantemesse, 
1896) and England. Certain places on the English littoral, in 
particular Belfast, Brighton and other towns, have for many 
years had endemic or residual typhoid cases, which form a very 
considerable per cent of the total number, and which may be in all 
probability traced to the eating of raw shell fish, oysters, mussels 
and cockles. Experiments on the resistance of typhoid bacilli 
when artificially placed in oysters show that they will survive for 
from five to nine days. 

Another indirect source of contagion from contaminated water 
is in the consumption of raw vegetables such as water cress, 
celery and radishes, which either have been washed with water or 
have been subjected to a forced growth by fertilization with night 
soil or contaminated water. 

One of the great sources of typhoid in its epidemic form is con- 



54 TYPHOID FEVER 

taminated milk. Milk comes to serve as a vehicle for the typhoid 
bacillus in three general ways. It may first of all be handled by 
carriers and so infected from their hands, and this infection may 
take place either on the farm, which is the more usual, or subse- 
quently during the transportation of the milk to market. This 
contamination of milk through carriers is perhaps the more usual 
and important means, and we have already mentioned its existence 
in another place, but milk may also be contaminated either through 
washing the cans in contaminated water or by actual adulteration 
with such water, usually from an infected well. The spreading of 
epidemics of typhoid through milk was mentioned as early as 1858 
by Taylor, and further insisted on by Ballard in 1870. Milk 
epidemics are characterized by occurring over the route supplied 
by some given milkman, and by the occurrence of several cases in a 
given house supplied with milk from this source. The disease 
itself occurs particularly in children and in women, who con- 
stitute the principal milk drinkers. The onset of the disease is 
characterized by a short incubation period, and its course is usually 
mild, which has been attributed to the attenuation of the path- 
ogenic properties of the microorganism through its growth in 
milk. Inasmuch as milk drinking is more or less of a luxury, milk 
epidemics occur more particularly in the families of the well-to-do. 
There is no question that epidemics and cases of typhoid through 
milk are considerable in number. Trask (Rosenau) in 1908 found 
a description of 317 milk epidemics, or something like 1900 cases 
in the United States alone. Schtider in Germany found that 
110 epidemics of the 640 which he has described were due to milk. 
Rosenau, who was concerned in the careful study of epidemics 
which occurred in Washington and which were investigated by the 
Public Health Service, thinks that something like ten per cent of 
all the cases for at least several years in that city were due to milk. 
Such a percentage of the total number of cases has been frequently 
accepted and quoted, but the figures are criticized by Chapin, not 
only on the basis of experience in other places, but on the basis of 
the figures in the Washington report itself; he is inclined to 
attribute a much smaller although still considerable role to milk 
in the spread of typhoid fever. Chapin, further, is inclined to 
question the generally accepted notion that milk epidemics are in 
part due to the fact that milk serves as a culture medium for the 
multiplication of the organisms originally contaminating it. There 
is no question, of course, but that sterilized milk is an admirable 
culture medium, but there are experiments which go to show that 
raw milk has during several hours at least a distinct inhibiting 



MODES OF INFECTION IN TYPHOID FEVER 55 

effect on the growth of the typhoid bacillus. As Chapin points 
out, if multiplication of the bacillus took place readily in milk, we 
should expect to find many more cases in the large cities due to this 
source, which, however, is not characteristic of such forms of the 
disease. Milk epidemics of typhoid spread rather over a short milk 
route in smaller towns, and there are practically none in the 
larger cities where milk is brought from a considerable distance 
and where much more time is allowed either for the multipli- 
cation of the organisms or, on the other hand, for their disap- 
pearance. 

Typhoid bacilli in milk are in all probability not readily killed 
when such milk is added in the ordinary proportions to tea or 
coffee, and such drinks may therefore serve as a further vehicle of 
infection in cases of this sort. 

8. Soil, Water or Food, Mouth. — We have incidentally con- 
sidered for the most part the features of an indirect transmission 
of the typhoid bacillus in this way in our consideration of the more 
direct route from water to the human body (Heading No. 6). This 
route is probably more usual, as we have already intimated, than 
from feces or sewage directly to water. The former route repre- 
sents more particularly the acute outbreaks of the disease, as we 
have stated. There are, however, certain prolonged epidemics 
which may be attributed to the further resistance of the typhoid 
bacillus in soil and its gradual and continual percolation into 
water sources. Chapin, who has thoroughly reviewed the exper- 
imental evidence as to the survival of Bacillus typhosus in the 
soil, concludes that these experiments show that although there is 
no multiplication in the soil, the organism may persist there for 
something like seventy-four days. Curschmann would lengthen 
this period to five and one-half months, and other authors would 
agree with him (Vincent and Muratet). 

Air and dust have both been mentioned as sources of infection in 
typhoid fever, more particularly in the early consideration of the 
transmission of the disease, as in the work of Budd and Murchison. 
It is probable, however, that most of the cases attributed to infec- 
tion of this sort were in reality contact infections, which in their 
lack of knowledge concerning the active agent in typhoid fever, 
these authors were unable to appreciate. The typhoid bacillus 
may survive drying and be alive in dust for considerable periods of 
time. There is not, however, any conclusive evidence that would 
show that transmission by dust through the air produces any 
considerable number of the cases of typhoid fever. 



56 TYPHOID FEVER 



Relative Importance of Various Routes of Infection 

As to some extent summarizing certain authoritative opinions 
on the relative percentages of cases of typhoid fever which may- 
be traced to definite sources, we may at this point present certain 
of them in tabular form. 





TABLE VI 






THE PERCENTAGE 


OF SOURCES 


OP TYPHOID 


FEVER 




Contact 


Water 


Milk 


Rosen au 


6-17 


35 


10 


Chapin 


10-40 


10-15 


0.2% 


Whipple 


30 


40 


25 


Kober 


— 


80 


— 


Spitta 


— 


33 


— 



Frosch 65 23.7 

It will be noted in this table that whereas there is marked differ- 
ence in opinion as to the number of cases which may be due to 
contact, there is more or less agreement as to the considerable 
number of cases, something like one-third, which are traceable to 
water. It is understood that these percentages represent, so far 
as these authors are able to estimate, the conditions of the present 
day. In former times the cases attributable to water are, as we 
have mentioned, far more numerous. 

GENERAL FACTORS WHICH INFLUENCE THE OCCURRENCE OF TYPHOID 
FEVER 

There are a number of factors which determine the success or 
failure of typhoid infection in its extension from one individual to 
another. These factors may be divided into two general cate- 
gories, extrinsic and intrinsic, in accordance with whether they are 
resident without or within the individual whose susceptibility to 
infection is determined by their resultant interaction. 

Extrinsic Factors. — Any condition operative on the life of the 
typhoid bacillus after it has left the human body tends markedly 
to affect its success in reaching and producing infection in a second 
individual. In general, the most important of these conditions are 
dependent on the directness of the route followed by the typhoid 
bacillus from one individual to another, which route in turn in- 
cludes the various factors which are antagonistic or favorable to 
the growth of the bacillus. These conditions have been fully dis- 



MODES OF INFECTION IN TYPHOID FEVER 57 

cussed in the previous sections of this chapter. It may in general be 
stated that any. unfavorable influence which tends to reduce the 
numbers or the virulence of the typhoid bacillus would markedly 
influence its possibility of producing typhoid fever. 

One of the most significant and earliest observed characteristics 
of typhoid fever is its seasonal occurrence. It has long been 
recognized that the disease occurs most frequently in late summer 
and autumn, although exception to this statement should be made 
in the case of epidemics due to gross pollution of water or food 
supplies, the causation of which is, indeed, indicated by their 
extra-seasonal occurrence. The reasons which underlie the char- 
acteristic seasonal occurrence of typhoid are by no means certain. 
Warm weather, particularly when combined with humidity, would, 
of course, provide a more favorable environment for the growth of 
the typhoid bacillus outside the body, but it seems certain that no 
such simple variation suffices to explain the predominance of 
cases during this season. It appears that not only the incidence but 
also the severity of typhoid cases is increased during warm weather. 
Three additional factors may be suggested as correlative with this 
increase in temperature: first, the larger number of flies which are 
present during this season; second, the increased consumption of 
liquids during warm weather; and, third, the vacation habit which 
leads to unaccustomed surroundings with ignorance of possible 
sources of infection. 

Geographical locality would seem to play little or no role in the 
occurrence of typhoid fever. The disease is ubiquitous, and 
epidemics have been described not only in the tropics but in equal 
number in temperate zones. And, again, the disease occurs in- 
discriminately in the plains and in the mountains, the ordinary 
variations in temperature, apart from seasonal variations, ap- 
parently having little effect on the occurrence of the disease. The 
ubiquity of typhoid fever is further evident in the fact that ap- 
parently all races of men are equally susceptible. It is true that 
certain authors have given evidence which would tend to show that 
some races, notably East Indians, Japanese and Arabs, may under 
certain conditions show an apparent insusceptibility to typhoid. 
The low morbidity rate of typhoid in a country like Japan, how- 
ever, may be more directly attributed either to dietary differences, 
or possibly to acquired immunity owing to more frequent incidence 
of the disease in childhood, rather than to a racial insusceptibility. 
In those other instances where it is apparently shown, as in the 
case of the Arabs, that the endogenous race is much less sus- 
ceptible than an alien race in the same country, the factor of non- 



58 TYPHOID FEVER 

acclimatization, which we shall presently consider, would seem 
of more importance than a relative racial insusceptibility. 

Intrinsic Factors. — It seems certain that under like external 
conditions with equal infecting doses no two individuals are 
equally susceptible to typhoid infection. This is evidenced by the 
fact, first, that in any given epidemic the severity of the disease will 
vary markedly from one individual to another, and, secondly, by 
the fact that under conditions of greatest exposure, whereas the 
majority of individuals fall victims to the disease, a small number 
remain uninfected. These variations in susceptibility are pri- 
marily individual, but may also in certain instances, as we have 
already mentioned, appear to be racial in character. The French 
authors in particular, for example Vincent and Muratet, and 
Brouardel and Thoinot, are inclined to attribute a real physiolog- 
ical difference in the defense of various races against the typhoid 
bacillus, but these differences, which undoubtedly are evident 
under certain conditions, would seem more easily attributed to 
variations in degree of exposure to infection or to acclimatization, 
as we have already stated. The most important factor affecting 
individual resistance to infection is the existence of immunity 
acquired either through recovery from the disease or through 
vaccination, the significance of which we shall discuss in a later 
place. The French authors we have mentioned further believe 
that a resistance of this sort may be acquired through a process of 
mithridatisation, brought about by the swallowing of repeated 
small doses which are insufficient to produce the disease but which 
give rise to a resistance to it. Apparently this conception exists in 
a less concrete form among many physicians who are inclined to 
attribute their failure to contract typhoid fever, in spite of great 
exposure, to constant association with typhoid fever cases. It 
would seem that evidence for an acquired immunity of this sort 
is no more than suggestive. 

The most important individual factor in determining suscep- 
tibility to infection with the typhoid bacillus is the question of 
age, as has been recognized by all competent observers. Infants 
are relatively insusceptible to typhoid, although the disease may 
occur in the foetus in utero and in a few instances in very young 
children. These instances are perhaps more frequent than is 
realized, owing to the mildness of the attack and to consequent 
failure in diagnosis. The incidence of the disease in all events in- 
creases very slightly from one to five years of age, but somewhat 
more markedly after this period to the age of puberty. The ma- 
jority of cases of typhoid fever may be grouped about the twenty- 



MODES OF INFECTION IN TYPHOID FEVER 59 

first year. According to Curschmann, four-fifths of all the cases 
occur between the fifteenth and thirty-fifth year. This author 
further finds that fifty-three per cent of his cases occurred be- 
tween the ages of fifteen and twenty-five, a figure with which 
Murchison essentially agrees, and from which statement there is 
no marked variation in the experience of other authorities. The 
incidence of the disease decreases markedly from the fortieth year 
onward, although the severity and morbidity rate increase. 

There is apparently some difference in opinion as to whether 
there is a varying susceptibility to typhoid infection in regard to 
sex. The majority of authors apparently have found no great 
difference in the number of males and females that have come 
under their observation. Others, for example Brouardel and 
Thoinot, and Curschmann, regard adult males as more susceptible 
than females of the same age. The latter viewpoint would seem 
more reasonable in view of the greater exposure to unguarded 
sources of infection to which the more active life of the male ex- 
poses him. Typhoid fever attacks particularly well nourished, 
active persons, apparently not only through their greater chances 
of exposure but also through some physiological difference which 
renders them more susceptible to the invasion of the bacillus. On 
the other hand, exhaustive diseases and other infections would 
seem to render individuals relatively less susceptible to infection. 
In a somewhat similar manner it has been generally agreed that 
pregnancy and lactation in women tend to render them less likely 
to be affected by the disease. Certain of the French authors would 
attempt to establish a family susceptibility to typhoid, owing to 
the undoubted fact that a number of cases may and frequently do 
occur in the same house. There seems no reason, however, to 
regard such occurrences as due to any cause other than greater 
exposure. 

Another interesting and apparently generally accepted cause of 
increased susceptibility is lack of acclimatization. It has been 
repeatedly noted that recent arrivals in large cities are more sus- 
ceptible to typhoid fever than the inhabitants. Louis found that 
seventy-nine per cent of his cases in Paris occurred in individuals 
who had lived for twenty months and less in the city, and Chomel 
in a somewhat similar manner found that sixty-seven per cent of 
his cases occurred in those resident for less than two years. A 
similar lack of acclimatization is evident in the city cases of vaca- 
tion typhoid, as they are called, which account for a considerable 
percentage of the cases in large cities which are rigorously careful 
in respect to their water supply. Here, of course, it is difficult to 



60 TYPHOID FEVER 

demonstrate conclusively that the city dwellers have acquired 
typhoid in the country because they were not acclimated, and a 
more reasonable explanation in most instances would be that they 
had suffered greater exposure in drinking of contaminated water 
supplies and the like. We find it somewhat difficult to accept the 
explanation which Vincent and Muratet, and Brouardel and 
Thoinot have offered for the cases due to non-acclimatization. 
These authors regard the preponderance of cases among recent 
arrivals in any given community as due to the fact that these in- 
dividuals, although they may be insusceptible to the strains of the 
typhoid bacillus in their home localities, are unaccustomed to the 
particular strains where they contract the disease. The most 
reasonable explanation for this group of cases must, we think, 
again be greater exposure and ignorance of proper water and food 
supplies. 

Work and fatigue, and possibly also psychic disturbances, such 
as anxiety and grief, may to some extent render the individual 
more susceptible to infection. 

Certain professions are distinctly more liable to typhoid fever 
than others. First among them are, of course, soldiers, and with 
them as with the other more susceptible professions, exposure 
again must be regarded as the most important factor. Soldiers, 
furthermore, in addition to the extreme danger from unguarded 
water supplies are particularly affected, owing to the fact that they 
are at precisely the age during which the majority of cases occur. 
They further suffer from the lack of acclimatization to which 
reference has been made, and are frequently exposed to fatigue and 
overwork. Washerwomen, particularly those engaged in the care 
of hospital linen, and nurses and physicians, who are in constant 
contact with typhoid cases are also very prone to take the disease. 



CHAPTER V 

THE PATHOGENESIS OF TYPHOID FEVER 

We are now in a position to consider more minutely that disease 
which the typhoid bacillus produces in the human body. As has 
been repeatedly intimated, we are not concerned in this treatise 
with a consideration of typhoid fever as a clinical entity awaiting 
diagnosis, but rather as a conflict between antagonistic elements 
represented by the typhoid bacillus and the human body. It is 
by this attitude that we conceive that the ultimate aims of di- 
agnosis and therapy are most successfully to be realized. For this 
purpose we shall follow the course of the typhoid bacillus in the 
human body so far as we may, rather than attempt detailed con- 
sideration of the symptoms of typhoid fever, except in so far as 
they may be employed in explaining the actual mechanism of the 
disease. 

GENERAL SYMPTOMATOLOGY OF TYPHOID FEVER 

As introductory, however, to a more detailed consideration of 
those phases of typhoid infection concerning which we may collect 
sequential data, we present at this point a brief and general outline 
of the symptomatology of the disease as a whole. The clinical 
picture of typhoid fever may be sketched chronologically as marked 
off into four more or less definite periods. During the first or 
incubation period, the nature of which will be more fully discussed 
presently, there are no definite, or at least no diagnostic or very 
indicative symptoms present. The distinctive symptoms of the 
disease are usually dated from the occurrence of actual fever, but 
there usually precede certain more or less well defined subjective 
disturbances which are briefly as follows: headache, listlessness, 
pain in the legs and back and anorexia, which may be extreme and 
be accompanied by nausea and even by vomiting. The initial 
symptoms are not infrequently ushered in by a chill. In general, 
it may be said that these premonitory symptoms are gradual rather 
than abrupt in their onset. 

The second period covers the first febrile period of the disease, 
and lasts, roughly, from a week to ten days. This period, known as 
the stadium incrementi (Jochmann), or the period of ascending 

61 



62 TYPHOID FEVER 

oscillations (Vincent and Muratet), is characterized by a gradually- 
rising temperature, which is higher each afternoon by a degree or 
so, and has morning remissions which may frequently fall to 
normal. During this period the temperature usually rises to a 
maximum of 103° or 104° F. This increasing fever is accompanied 
by a slow pulse of 100 to 110 which is of low tension and char- 
acteristically dicrotic. As subjective symptoms may be noted 
vertigo, buzzing in the ears, headache, which may be severe, and a 
gradually increasing apathy and feeling of weakness. Epistaxis is 
not infrequent but by no means regular. The abdomen becomes 
distended, the tongue is white and furred and the bowels may 
either be constipated or diarrhea may be present. Not infre- 
quently slight rales over the chest give evidence of a mild bron- 
chitis. The leucocytes frequently are slightly increased in number 
to a count of perhaps 10,000 to 11,000 to the cubic millimeter. 
This period is accompanied by the beginnings of those pathological 
changes which are characteristic of the disease. The patches of 
Peyer show hyperemia followed by hyperplasia; the solitary 
follicles also begin to project beyond the surface of the intestine; 
the mesenteric lymph nodes are swollen and reddish; the liver is 
enlarged and hyperemic; and the spleen also begins to enlarge 
during this first febrile period. 

The third period of the disease represents the febrile plateau 
during which the temperature is at its maximum, 103° to 105° or 
even more, and is not characterized by any considerable remission 
during the course of the day. This is the stadium acme, so-called, 
or fastigium. It lasts, roughly, through the second and third 
weeks. During this period the headache usually becomes less, 
but the mental processes are cloudy, giving rise to the charac- 
teristic typhoidal condition (tC«£os, a cloud). The apathy in- 
creases and delirium may become more or less marked, particularly 
at night. Diarrhea is usual and the excreta become more fetid. 
Tympanites may become marked. The tongue is brownish and 
dry. Ulcerations may occur in the pharynx and mouth. The en- 
larged spleen becomes clinically palpable. Rose spots occur in the 
majority of cases, either singly or in small successive crops. The 
blood picture is characterized by a leucopenia with a relative in- 
crease of the mononuclear cells and absence of eosinophiles. The 
loss of weight becomes considerable. The pulse is more rapid and 
less dicrotic in quality. 

The lesions of the disease during this period go on in their char- 
acteristic evolution. The swollen Peyer's patches become necrotic 
and sloughing, with small ulcers which usually coalesce and extend 



THE PATHOGENESIS OF TYPHOID FEVER 63 

lengthwise of the gut, frequently penetrating to the submucosa or 
the muscularis. The mesenteric lymph nodes are still more 
swollen but grayish in color and show patches of necrosis. The 
liver becomes less hyperemic and rather flabby, and shows on 
section small grayish nodules which are found to be due to col- 
lections of proliferated endothelial cells. Parenchymatous degen- 
eration is also present in both liver and kidney. The spleen in- 
creases to its maximum size, which is from one and one-half to 
three times the normal. Hemorrhage and perforation are among 
the complications which may occur during this period. 

The latter period of the disease, extending usually from the third 
week onward, is characterized by a falhng temperature, and is 
known as the stadium decrementi or the period of descending 
oscillations. The afternoon maximum decreases by fractions of a 
degree daily, and the morning temperature falls more rapidly until 
it reaches normal or even subnormal. The mouth and tongue be- 
come clean. Polyuria takes the place of suppression of urine, 
which may have occurred previously, and the appetite gradually 
returns. Necrosis of the intestinal lesions may increase and lead 
to hemorrhage and perforation, failing which, in favorable and 
usual cases healing begins to take place. 

The actual complications, hemorrhage, perforation, and par- 
ticularly relapse, may occur after several days of normal tempera- 
ture, and the other sequels, thrombosis, osteomyelitis, cholecystitis 
and the like, which we will discuss in more detail, also take place 
during or following this convalescent period. 

THE INCUBATION PERIOD 

In common with all other infectious diseases, there occurs a 
definite incubation period following the ingestion of typhoid 
bacilli, before the development of the symptoms of the disease. 
This incubation period, in the case of diseases whose causative 
agents enter the body through the gastro-intestinal tract, and 
subsequently invade the entire body, should, properly speaking, 
be regarded as beginning when the microorganism leaves the 
gastro-intestinal tract through some portal of entry to initiate the 
process which characterizes its presence in the body. The mere 
presence of the microorganism in the gastro-intestinal tract should 
theoretically not be regarded as the beginning of the disease it- 
self, any more than the presence of the tetanus bacillus on the 
skin of the body would be so considered. Owing to the difficulty, 
or, indeed, the impossibility in most instances of determining the 



64 TYPHOID FEVER 

exact moment at which the typhoid bacillus enters the body- 
proper from the intestine, it has been customary to regard the 
incubation period as beginning with the ingestion of the micro- 
organisms. And even in this case the estimation of this latent 
period is more difficult in the case of typhoid fever than in almost 
any other disease, excepting in those instances where known con- 
taminated food or drink has been ingested. 

The simple presence of typhoid bacilli in the intestine does not 
in itself constitute infection with the typhoid bacillus, as is evi- 
dent from a consideration of those healthy and recovered carriers 
who show no symptoms of the disease. In other words, the or- 
ganism may live as a saprophyte in the intestine for indefinite 
periods without initiating any disease process. 

The usual period of time between ingestion of material con- 
taining the typhoid bacillus and the occurrence of the first symp- 
toms of the disease has usually been regarded as between ten days 
and two weeks. Curschmann states the incubation period to 
be one to two or three weeks, Murchison two weeks or more, 
and McCrae three to twenty-three days. The possibility of a 
short incubation period has been recognized very distinctly since 
the time of Budd, 2 who speaks of a series of cases in which the 
incubation period seemed definitely to have been about four days. 
Murchison also speaks of cases with a short incubation period, 
although his information seems to be less definite regarding them 
than was Budd's. The acceptation of the classical two weeks 
interval would seem to be founded on somewhat indefinite evi- 
dence and on a basis of cases in which the transmission has been 
through contact or water pollution. In both these instances we 
have reason to believe that the actual number of bacteria ingested 
is relatively small, and more recent experience shows not only 
that the incubation period may be as short as Budd has stated, 
but that the actual duration probably bears an indirect relation 
to the number of bacteria that have entered the gastro-intestinal 
tract. 

In the case of laboratory infections it is easier not only to esti- 
mate the number of bacteria that have been swallowed, but to 
know with great accuracy the time at which the organisms were 
actually taken into the body. Kisskalt's ' study of cases of ty- 
phoid laboratory infections apparently does not bear out the 
idea that the incubation period is shortened by a large dose of 
bacteria. In a careful summary of fifty cases of this sort in which 
the mode of infection was in the most instances known, the usual 
duration of the incubation period was about fourteen days, al- 



THE PATHOGENESIS OF TYPHOID FEVER 65 

though there are cases of five, six and eight days recorded. In 
these cases it must be taken into consideration that although the 
original dose consciously taken into the mouth was usually large, 
vigorous efforts were made in most instances to destroy the in- 
gested bacteria, which must at least have been to some extent 
successful. 

In a case which occurred in our own laboratory an assistant, 
while injecting a goat with a thick suspension of mixed living cul- 
tures of recently isolated typhoid bacilli, received through the 
spurting of a temporarily blocked syringe a considerable amount 
of the injection mass on the left cheek and conjunctiva. Two 
days later she felt distinct malaise, and on the fifth day was ill 
in bed with a temperature of 104°, at which time the typhoid 
bacillus was isolated from the circulating blood. In the epidemic 
reported by Sawyer in Hanford, California, of ninety-three people, 
who had partaken of a dish of Spanish spaghetti which had been 
prepared by a typhoid carrier the day previous to eating, and in 
which the bacteria had multiplied by a process of incubation, as 
was subsequently shown by laboratory experiments, over half of 
the cases showed symptoms before the eighth day, the first one 
on the third day, twelve on the fifth and nineteen on the sixth. 
Epidemics caused by contaminated milk, when compared with 
those produced by contaminated water, are characterized by 
suddenness and violence of onset (Whipple). It is well known 
that whereas typhoid bacilli tend to decrease in polluted water, 
they increase rapidly in milk, which serves as an admirable cul- 
ture medium. 

This probable relation between the size of the infecting dose 
and the shortness of the incubation period renders Vaughan's 2 
admirable hypothesis of fever still more acceptable. Vaughan 
has assumed that the incubation period preceding the onset of 
fever in the infectious diseases is due to the lapse of time required 
for the formation of specific proteolytic ferments, the subsequent 
action of which on the bacteria liberates poisons which cause the 
fever. Under usual conditions of infection with small dosage it 
would take the classical ten days interval for the production of 
effective ferments, just as it does for the maximum formation of 
antibodies under conditions of artificial immunization. We 
know, however, that this antibody formation may be markedly 
accelerated. Strong hemolysins, for instance, can be formed in 
four or five days when proper doses of blood are given animals 
intravenously (Gay and Fitzgerald). Smith has claimed that the 
antibodies responsible for the Abderhalden reaction may actually 



66 TYPHOID FEVER 

be produced in a few hours. The modern work on protein therapy 
which is assuming significance, as we shall later see, in typhoid 
and other acute infections, would seem unquestionably dependent 
on the rapidity with which ferments of this type can be mobilized. 
The condition of antityphoid immunity is perhaps best explained 
in a similar manner. 

THE PORTAL OF ENTRY 

The typhoid bacillus may be found at almost any point in the 
gastro-intestinal tract during the course of the disease. Drigalski 1 
obtained pure cultures from the tonsils and tongue, and also from 
the stomach, in spite of the acid reaction there present. Indeed, 
it has been shown that small amounts of hydrochloric acid have 
very little effect on the growth of the typhoid bacillus (Kitasato). 
There is, however, no reason to believe that the typhoid bacillus 
actually increases in numbers anywhere in the intestinal canal 
(Forster *). The evidence, indeed, is quite to the contrary. Dur- 
ing the latter stages of the disease, when the organisms are present 
in large numbers in the feces, it may still be shown that the num- 
bers in the lower part of the canal are much smaller than in the 
upper portions. Cultures taken at successive levels by Drigalski 
and by Forster and Kayser l have shown that whereas the typhoid 
bacillus is present in practically pure cultures in the duodenum, 
it decreases in numbers and purity as one descends toward the 
lower end of the small intestine and into the colon. This diminu- 
tion is brought about not only by a failure of the organism to 
multiply, but by the antagonism of the colon bacilli normally 
present in the canal. It has recently been found by Nissle * that 
strains of colon bacilli differ markedly in their antagonistic effect 
in symbiosis with typhoid bacilli, those strains which produce the 
greater amounts of lactic acid giving the higher "antagonistic 
index," and he has actually suggested the importation of such 
active strains of the colon bacillus in combatting, or, indeed, in 
preventing typhoid fever. It may be that the failure to produce 
a septicemia with Bacillus typhosus in the smaller laboratory 
animals in feeding experiments is due to a still more active an- 
tagonism of this sort (Bezzola and Vallardi). The overgrowth of 
colon bacilli may be favored by a carbohydrate diet, which is one 
of the reasons for the success that has attended the recent methods 
of high calory treatment in typhoid. 

The small number of typhoid bacilli which constitute the orig- 
inal infecting dose are in all probability either soon destroyed or 
absorbed through the portals of entry. At all events, they do 



THE PATHOGENESIS OF TYPHOID FEVER 67 

not usually occur in the excreta in sufficient numbers to be found 
on ordinary examination. We know that the percentage of cases 
in which the examination of the feces becomes positive increases 
with the duration of the disease, being greatest during the necrotic 
period of the intestinal ulcers, roughly, from the eleventh to the 
twentieth day of the fever. Their occurrence in large numbers 
during the stage of necrosis has no direct relation to the necrosis 
itself, for the organisms do not multiply to any extent in the 
necrotic areas, nor are they primarily eliminated through them. 
There is no question that the numerous organisms in these latter 
stages of the disease have been excreted with the bile into the 
intestine. They reach the gall bladder, as we shall see, from the 
circulation. It may happen that the typhoid bacilli in the bile 
are not present in large enough numbers to survive until they 
reach the cecum and so be detected in the stools, until very late 
in the disease. Instances have been reported by Conradi 2 in 
which they were not found until eleven to eighteen weeks after 
the first symptoms. On the other hand, it is known that they 
may exceptionally occur during the incubation period of typhoid 
fever (Conradi, 2 Mayer. 1 ). These individuals who excrete the 
typhoid bacilli before they show evidence of the disease constitute 
the so-called precocious carriers, which from the standpoint of 
hygiene are the most dangerous ones in producing contact infec- 
tions, owing to the fact that they are not recognized to be dan- 
gerous. Conradi 1 found that fifty-eight per cent of the contact 
infections from typhoid cases occurred in the first week. The 
early occurrence of the typhoid bacillus in the stools of such in- 
dividuals does not, however, in any way reverse our statement as 
to the failure of the organisms to multiply in the intestine. It 
simply means that the organisms have entered the body proper 
from the intestinal canal, have actually multiplied there, in all 
probability have been present in the circulating blood, and have 
in all events been eliminated through the gall bladder precisely 
in the fashion that regularly takes place later in the course of the 
fever. 

The mere presence of the typhoid bacillus in the gastro-intestinal 
tract of man is not sufficient to cause typhoid fever. We have 
evidence of this fact from our knowledge concerning the existence 
of healthy carriers, individuals who have never suffered, so far 
as known, from typhoid fever, who in the majority of cases show 
no evidence in their blood serum reactions that they have under- 
gone such an infection, and yet harbor the typhoid bacillus in 
their intestines. The absence of a history of typhoid fever, how- 



68 TYPHOID FEVER 

ever, does not preclude the possibility that the typhoid bacillus 
has actually passed through the body of such an individual, with- 
out causing the characteristic symptoms of the disease. Simple 
gastro-intestinal upsets with or without a fever are undoubtedly 
in some instances true cases of typhoid infection, and it is known 
that the typhoid bacillus may reach the gall bladder presumably 
through the circulation, without calling forth or before evoking 
any definite symptoms of typhoid fever. Perfectly healthy in- 
dividuals have indeed been detected with typhoid or paratyphoid 
bacilli in the circulating blood (Conradi, 2 Busse, Mayer, and 
Ebeling). 

It has frequently been assumed that the lower part of the small 
intestine, particularly those structures which respond characteris- 
tically to typhoid infection, namely, Peyer's patches, represent 
the portals of entry in the disease, but whatever proof of this 
exists is essentially indirect. The infecting microorganism must 
proceed somewhere from the gastro-intestinal tract to the internal 
organs, there to set up the lesions and to evoke the symptoms 
which are characteristic of this malady, but it is by no means cer- 
tain that the usual lesions of Peyer's patches have anything to 
do with the entrance of the microorganism. These lesions are in 
all probability eliminative in character, and probably are evident 
only after the microorganism has gained a hold in the general 
circulation, and with certainty only after the actual entrance of 
the microorganism into the body from the gastro-intestinal tract. 
It has been shown experimentally by Ribadeau, Dumas and 
Harvier that typhoid bacilli are excreted into the intestine after 
intravenous injection through the intestinal wall, and particularly 
in places that are rich in lymphoid tissue like the appendix. It is 
interesting in this connection to note that appendicitis, particu- 
larly of a mild degree, is of relatively frequent occurrence in typhoid 
(Hare and Beardsley). According to Wolfsohn, 1 appendicitis 
due to Bacillus typhosus may be the only evidence of typhoid 
in individuals rendered resistant through vaccination. 

It has been suggested by some observers that the tonsils or 
lymphoid structures in the pharynx may represent the true por- 
tals of entry. Drigalski ' reports an epidemic which he studied 
in which forty per cent of the cases began with an angina, and he 
was able to obtain pure cultures from the throat in most of his 
cases. Tonsillitis and sore throat are not infrequent beginning 
complications of typhoid, and have been noted repeatedly since 
the classical works of Louis and Jenner. 3 A number of other writers 
have mentioned the tonsils as possible portals of entry (Brion and 






THE PATHOGENESIS OF TYPHOID FEVER 69 

Kayser) . Curschmann * is inclined to regard tonsillitis as an 
unusual accompaniment of typhoid, although he found it with 
great frequency in certain epidemics. Further attention has been 
drawn to the upper part of the gastro-intestinal tract as a possible 
portal of entry by the occurrence of ulcers in the pharynx, as 
noted by Louis, f Jenner, 3 J and Klebs. 3 

Whatever may be the exact point of entrance of the micro- 
organism, it seems fairly certain that the lymphoid apparatus, 
whether of the pharynx or of the intestine, is the first structure 
affected, and remains the characteristic point of localization of the 
typhoid infection (Kolle and Hetsch; Sanarelli, Jochmann, and 
Kutscher). The mesenteric lymph nodes apparently are swollen 
before any visible change has taken place in the intestinal mucosa, 
and, granting that the portal of entry lies through this mucosa, 
it seems certain that the entrance may take place without any 
visible lesion (Meyer). Cases of typhoid without intestinal lesion 
have been reported in considerable numbers (Posselt x ), and will 
later be considered in other connections. Such cases are not in- 
frequently characterized by swollen mesenteric nodes, even when 
there are no lesions in the intestines (Chiari and Kraus). Of 
course, the failure to find any macroscopically visible lesion of 
the intestinal mucosa does not rule out minute abrasions which 
might be sufficient to allow the entrance of the typhoid bacillus. 
An ancient idea of the causative relation between intestinal worms 
and susceptibility to typhoid has been recently brought forward 
again by Barabaschi. In this author's experience oxyuris or tri- 
chocephalus were present in the intestines of ninety-six per cent 
of his typhoid cases, whereas in healthy people they occurred in 
only twenty-one per cent, and he suggests that they injure the 
mucosa sufficiently to allow easier penetration of the bacillus. 
Considering the widespread susceptibility of unprotected in- 
dividuals to typhoid infection, as evidenced in epidemics, the as- 
sumption of some necessary injury to the mucosa to permit infec- 
tion seems superfluous. Apart from the fact that the mesenteric 
nodes may be swollen without any evident portal of entry, it has 
also been shown that these nodes are the first to be swollen in the 
course of the disease (Baumler), thus indicating clearly that they 
are the first affected. Levy and Gaethgens found, moreover, that 
while cultures from the mesenteric glands in typhoid autopsies 
were invariably positive, and while they were nearly always ma- 
croscopically changed, they frequently failed to find the micro- 
organisms in other lymph nodes. Banti succeeded in isolating 

* Loc. at., p. 202. f Loc. cit., p. 135. X Loc. cit., p. 63. 



70 TYPHOID FEVER 

the typhoid bacillus from the spleen and lymph nodes in a case 
which showed no other lesions. Southard and Richards have 
described a case of typhoid meningitis with recovery of the or- 
ganism from the brain and mesenteric lymph nodes only. The 
latter were swollen and were the only organs suggesting typhoid 
fever at autopsy. 

LOCALIZATION OF THE TYPHOID BACILLUS IN THE BODY DURING THE 
COURSE OF THE DISEASE 

The lymphoid apparatus of the small intestine is, then, the 
beginning and the most characteristic localizing point of typhoid 
infection. The changes in the mesenteric lymph nodes, as evi- 
denced by visible enlargement, must be of very early occurrence in 
the disease. Delafield and Prudden report an autopsy in the 
forty-seventh hour of the disease where the only lesion found was 
such a nodular swelling. The changes in the finer structure of the 
lymph nodes in typhoid fever is at once interesting and of con- 
siderable significance in throwing light on the mechanism of the 
process itself. We are indebted primarily to Mallory l for having 
pointed out the exact nature of the changes in the lymphatic sys- 
tem in typhoid fever. He has described with great minuteness the 
structure of those nodular swellings or "lymphomata," as they 
had been previously called, which he finds due not to proliferation 
of lymphoid but of the endothelial cells in the lymph nodules. 
These cells show signs of active mitosis wherever they occur in the 
spleen, lymph nodes, liver or bone marrow. Mallory's supposition 
that the cause of this proliferation is the liberation and action of 
endocellular toxin from the typhoid bacillus is perhaps correct, al- 
though he brings forward no experimental evidence in its support. 
The limitations of the histological method are evident in those ob- 
servations, which lead him to state that the typhoid bacillus is not 
characteristically present in these specific lesions. The exact con- 
trary may be shown to be true, as we have already stated, when 
systematic cultures are taken from these nodes and compared with 
cultures from any other part of the body. It becomes evident that 
the lymph nodes remain, in conjunction probably with the bone 
marrow and gall bladder, and perhaps the spleen, the reservoirs 
and foci of proliferation of the typhoid bacillus throughout the 
course of the disease. 

It is of great importance to identify more certainly these res- 
ervoirs of the typhoid bacillus, as throwing light upon the mech- 
anism of the disease. The typhoid bacillus is found, as we know, 



THE PATHOGENESIS OF TYPHOID FEVER 71 

in the circulating blood at almost any period in the course of the 
disease, but more particularly in its early stages. The organisms 
multiply probably in the lymph nodes and overflow into the circu- 
lation, whence they are swept to various other parts of the body, 
there to be destroyed, or by a metastatic process to give rise to 
additional foci of re-infection. The typhoid bacillus has been 
found in the thoracic duct, presumably en route from the lymph 
nodes to the general circulation (Dehu). We shall later consider 
in more detail the percentages of positive blood cultures at different 
stages in the fever in connection with the chapter which deals with 
diagnosis. Suffice it to state here that the bacillus on entering the 
body from the intestine reaches the general circulation with great 
rapidity, probably during the incubation period, as has already 
been mentioned, and is practically always to be found there in the 
earliest stages of the fever. It is probable that in healthy carriers 
who give no history of typhoid fever the typhoid bacillus may have 
passed through the general circulation and into the gall bladder, 
where we know that it continues to proliferate and thereby to 
account for the permanent or temporary dissemination of the 
germs. This probability is rendered more likely by our knowledge 
of the occurrence of primary gall bladder infections with or without 
subsequent typhoid fever (Posselt *). 

The almost constant finding of the typhoid bacillus in the blood, 
and, particularly, its presence even in those cases without char- 
acteristic intestinal lesions, has led to increasing agreement in re- 
garding this infection as a septicemia or bacteremia. The two 
terms have been used indiscriminately. It is called a septicemia by 
Posselt, Besancon and Philibert, 1 and by Sanarelli, and a bac- 
teremia by Drigalski, by Kolle and Hetsch, by Jochmann and 
others. The latter term is undoubtedly the correct one, if we ac- 
cept the opinion of Roger that bacteremia should be employed to 
include both septicemia and pyemia; in other words, any condition 
in which the microorganism occurs both in the blood stream and in 
localized or metastatic foci. Such is precisely the condition which 
occurs in typhoid fever where the microorganism, although not 
multiplying in the circulating blood, is found there very frequently. 
It not only fails to multiply in the blood but is destroyed there, and 
in all probability with great rapidity, since it is known that even 
normal human blood has the property of destroying the micro- 
organism, a property which is increased during the course of the 
disease in proportion to the success with which the individual 
reacts to the invading pathogenic agent. This increase in bac- 
teriolytic power accounts for the failure to obtain cultures with 



72 TYPHOID FEVER 

so great frequency in the latter stages of the disease, excepting 
in those cases of grave or fatal prognosis. Jochmann has laid 
great emphasis on the number of resistant typhoid bacilli as ob- 
tained in plates from the circulating blood, as indicating the 
actual condition and prognosis of the individual case, and there 
is some evidence from the observations of Flexner to believe that 
the typhoid bacillus rapidly increases in the terminal stages of 
fatal cases, when the bacteriolytic activity of the blood dimin- 
ishes. This is further indicated by the work of Schottmuller, * 
who found that in the fatal cases there is a progressive rise in the 
number of colonies to death. 

General experience further agrees with Schottmuller that the 
typhoid bacillus is not found in the circulating blood after the 
end of the afebrile period of typhoid fever. The difficulty lies in 
explaining the persistence of the fever after the blood culture has 
become sterile, which is the regular occurrence in every recovering 
case. The fall in the number of bacteria in the circulating blood 
as the disease progresses is accompanied in a general way by a 
rise in the antibodies likewise present, at least in so far as they may 
be determined from the content of the serum in agglutinins. This 
would seem to suggest that typhoid bacilli continue to enter the 
circulation from the reserve foci in lymph nodes, spleen and bone 
marrow, but are so rapidly destroyed as to render blood cultures 
sterile, although, and indeed through this rapid destruction, the 
fever persists. Schottmuller has also shown that in some cases 
recrudescences in the fever may be accompanied by reappearance 
of the organism in the blood. 

The Cause of the Fever in Typhoid. — The destruction of the 
microorganism in the circulating blood in large numbers is very 
probably the cause of the fever which is so characteristic an ac- 
companiment of the disease process. According to Vaughan, 1 it is 
the successive splitting of foreign proteins which would account for 
fever in general, and he has been able to produce a similar con- 
tinuous fever in rabbits by the injection of a relatively harmless 
foreign protein, egg white, an observation which was extended by 
Friedberger and Mita, who obtained similar results with bacterial 
proteins. In agreement with this hypothesis are the observations 
of Bergey which show that the pyrogenic action of the typhoid 
bacillus is due to intracellular rather than to soluble toxins. It 
should not be overlooked in this connection that afebrile forms of 
typhoid of undoubted authenticity have been described by nu- 
merous authors and succinctly presented by Hare and Beardsley. 
These cases frequently present all the other characteristic signs of 



THE PATHOGENESIS OF TYPHOID FEVER 73 

the disease, positive blood cultures and Widal, enlarged spleen, 
roseola, and the like, and may be quite as severe as the ordinary 
febrile cases. So far as we are aware, no explanation of this 
anomalous form of the disease is forthcoming. 

Metastatic Foci of Typhoid Bacilli. — Typhoid bacilli that have 
entered the circulating blood from the original foci in lymph nodes 
are then spread in a metastatic manner to various parts of the 
body, with predilection for certain tissues. Among these tissues 
are lymph nodes, bone marrow, gall bladder, spleen, periosteum, 
and kidneys. They are present also in the rose spots, where they 
occur not in the blood vessels but in the connective tissue spaces 
(Kolle and Hetsch). These multiple foci where the bacteria suc- 
ceed in multiplying serve as reservoirs for continuous re-infection 
or re-invasion of the circulation, with continuance of the fever, for 
recrudescences of the disease in the form of relapse, and for the 
production of complications and sequels, and are of still greater 
general significance in the spread of the disease through carriers. 
It is interesting to note that when these tissues are properly stained, 
the bacteria in the metastatic foci appear characteristically in 
clumps which are often of considerable size. 

We may consider in some detail the individual significance of 
these various metastatic foci. The continued presence of nests 
of the typhoid bacilli in the lymph nodes, the spleen and bone 
marrow, is characterized, as we have already mentioned, in the 
majority of cases of typhoid fever by the appearance of certain 
definite and well recognized, specific lesions in the nature of en- 
dothelial proliferation. These reactions may be simple reactions 
of injury, but more likely represent a purposeful multiplication of 
those cells (macrophages) which we may suspect have to do with 
the elaboration of antibodies. Reactions of this type and the oc- 
currence of those characteristic lesions in Peyer's patches which 
are dependent upon this endothelial proliferation are no indication 
of the severity of the infection itself (Jochmann). Indeed, it is 
probable that proliferation of the endothelial cells is a beneficial 
process and indicative of successful resistance. The ulceration 
of Peyer's patches is largely a mechanical affair brought about, 
as Mallory has shown, by the shutting off of the blood supply in 
these areas through occlusion of the vessels by these endothelial 
masses, and to some extent aided by the action of the endo- 
toxins of the typhoid bacillus. Fatal terminations in typhoid 
fever through hemorrhage or perforation must be regarded as 
accidents of the disease rather than indications of the severity 
of the infection, such as is truly represented by those deaths 



74 TYPHOID FEVER 

designated as due to toxemia. It would be interesting in this 
connection to know more definitely the severity of those unusual 
cases of typhoid fever which are characterized by a septicemia 
without intestinal or other specific lesions. That they may be 
severe is, of course, evident from the fact that the only ones we 
have recognized have had a fatal termination, and whether such 
atypical cases occur with greater frequency in recovered individuals 
cannot, of course, be determined. At all events, these three 
organs, bone marrow, spleen and lymph nodes, are the organs 
where, next to the gall bladder, typhoid bacilli are found with 
greatest regularity at autopsy, even in those cases where the cir- 
culating blood is sterile (Kutscher). Similar results have been 
obtained by Ludke x in inoculated guinea pigs, who found that the 
bacteria are present in the spleen and bone marrow where they 
increase after they have left the circulating blood, which he re- 
gards as similar to the condition during the latter stage of human 
typhoid fever. In unreported experiments from this laboratory 
it has been found that the chronic typhoid carrier state in rabbits 
following intravenous injection is characterized by persistence of 
typhoid bacilli in large numbers, not only in the gall bladder but 
also in the bone marrow. Whereas the bacilli are found for the 
first few days in spleen, lymph nodes, blood, bile, and bone marrow 
indifferently, they soon disappear from the blood, lymph nodes 
and spleen as the agglutinins rise in the serum. On the other 
hand, they increase in the bile and bone marrow, where enormous 
numbers are evident in plates. This condition would seem to 
offer still further analogy between this rabbit condition and human 
typhoid (Gay and Claypole ] ). Quincke and Fraenkel have both 
obtained positive cultures from the bone marrow with regularity 
in cases of typhoid. 

The Bone Marrow in Typhoid 

The organisms may continue to multiply in the spleen and bone 
marrow, and perhaps also in the lymph nodes, even after the 
temperature has returned to normal. There would seem to be 
definite relation between the persistence of splenic tumor and the 
occurrence of a relapse (Sterzing). The bone marrow is of par- 
ticular interest in relation to sequels of the disease, particularly 
those of a surgical nature, which in this localization take the form 
in decreasing frequency of periostitis, necrosis and caries (Keen). 

There would seem to be a direct relation or sequence in the elec- 
tive affinity of the typhoid bacillus for the bone marrow, the changes 
produced in the cells there, and the characteristic leucocyte pic- 



THE PATHOGENESIS OF TYPHOID FEVER 75 

ture in the well developed disease. Longcope has made a detailed 
study of the bone marrow changes in typhoid and found them 
to consist of hyperplasia of the lymphoid cells and endothelial 
phagocytes as in the lymph nodes, and in the presence of dissemi- 
nated necroses. In the cases that were complicated by perfora- 
tion and peritonitis diffuse degenerative changes of the blood- 
forming cells with marked edema and congestion were added to 
this picture. 

In direct sequence would follow the characteristic blood pic- 
ture of leucopenia, relative increase of large mononuclear cells 
and aneosinophilia which, as pointed out by Naegeli and by 
Thayer, occurs in ninety-five per cent of all cases and is of diagnos- 
tic value. The leucocytes, which may show a slight increase 
early in the disease, by the second week fall to four to five thousand, 
and may in extreme cases reach two thousand or below. We have 
seen one case with complicating laryngitis and later pneumonia 
in which the count was one thousand only, some days before a 
fatal termination. 

A sudden rise in the leucocytes may be indicative of a complica- 
tion, although it has been shown by Kast and Gutig and by Long- 
cope that this is by no means the rule. Even perforation with 
general peritonitis, according to these authors, usually fails to 
cause a rise of leucocytes above seven thousand. A gradual re- 
turn of the leucocyte count to normal, in particular when asso- 
ciated with the re-appearance of eosinophiles, is indicative of re- 
covery. The sharp leucocytic crisis artificially induced by the 
intravenous injection of typhoid vaccine is, as we shall later see, 
frequently accompanied by temporary or permanent symptomatic 
benefit in practically any stage of the disease. 

The Gall Bladder in Typhoid Fever 

The most interesting metastatic focus in the body, both in 
relation to the course of the disease itself and particularly in rela- 
tion to its sequels, is the gall bladder. The liver and the bile have 
certain very definite antagonistic action against certain invading 
microorganisms (Posselt 2 ). It would appear that the inhibiting 
effect of the liver on bacterial growth is due to its action as a blood 
filter and also to its content in bile. Bile seems to have definite 
bactericidal effect upon certain microorganisms such as the strep- 
tococcus, pneumococcus and the tubercle bacillus (Zehden). On 
the other hand, organisms of the colon-typhoid group, and par- 
ticularly the typhoid bacillus seem to have a peculiar affinity 
for the gall bladder and for bile. Reference has already been 



76 TYPHOID FEVER 

made to the rapidity with which the typhoid bacillus may be 
found in the gall bladder in cases of human typhoid infection. 
The very first symptoms, and indeed the only symptoms, of 
typhoid infection may be referable to the gall bladder by the oc- 
currence of jaundice (Posselt x ), by cholecystitis, by the occur- 
rence of a liver abscess, or by localized peritonitis due to perfora- 
tion. In the majority of cases, however, the typhoid bacillus 
reaches and remains in the gall bladder without evoking either 
immediate or delayed symptoms. At all events, the bacilli are 
present in the gall bladder in practically every case of typhoid 
fever (Chiari'' 3 ; Kolle and Hetsch; Forster and Kayser; and 
Kutscher). It is now generally agreed that the organisms reach 
the gall bladder through the circulating blood in a descending 
fashion, originally pointed out by Chiari 4 on the basis of human 
cases, and later through the study of a similar condition in rabbits. 
In studying the latter condition it was found by Chirolanza that 
rabbits given an injection of typhoid bacilli in the vein would 
show the microorganism in the gall bladder in at least two hours, 
and even when the cystic duct was tied. We have obtained similar 
results within half an hour. 

The typhoid bacillus reaches the gall bladder promptly through 
the circulation, and, as we have stated, even in cases which show 
no symptoms of typhoid fever. This, we believe, accounts for 
the production of healthy carriers. The condition of precocious 
carrier, which may occur in the incubation period of typhoid 
fever, is likewise undoubtedly due to the fact that the typhoid 
bacillus has already entered the general circulation and been 
eliminated in increased numbers through the gall bladder even 
before symptoms of the disease occur. We know, furthermore, 
very definitely that the increasing numbers of typhoid bacilli 
during the course of typhoid fever are due to the increasing mul- 
tiplication and elimination through the bile into the intestine, as 
is clearly evidenced by the repeated observations, to which we 
have referred, that show that there are more organisms present 
in the upper sections of the intestine than in the lower. There 
is evidence that although bile in its original condition may not 
inhibit the growth of the typhoid bacillus, it becomes an even 
more favorable medium for its growth through the deposition 
of certain albuminous substances caused by the growth of the 
organism in the walls of the gall bladder. Perhaps the greatest 
significance of the occurrence and growth of the typhoid bacillus 
in the gall bladder lies in relation to its persistence there after 
recovery from the disease, with its etiological importance in the 



THE PATHOGENESIS OF TYPHOID FEVER 77 

formation of gall stones, and in the production of the temporary 
or permanent carrier condition. 

THE TOXINS OF THE TYPHOID BACILLUS IN THEIR RELATION TO THE 
DISEASE PROCESS 

We have spoken of the toxins of the typhoid bacillus in the third 
chapter and have incidentally attributed certain of the results of 
human infection, such as fever and the like, to these toxins, but 
have for the most part been concerned in the localization and 
multiplication of the microorganism itself in the body. Any 
toxin production must, of course, presuppose and be dependent 
on the growth of the bacillus itself, or, perhaps better, on its de- 
struction and disintegration, which thereby liberates its endotoxins. 
Certain symptoms and results in typhoid fever have been attrib- 
uted directly to toxins, and we may question indeed if all symp- 
toms are not really referable to these somewhat indefinitely under- 
stood substances. Headache, fever, circulatory disturbances, 
the nervous and mental manifestations of the typhoidal state 
seem definitely toxic symptoms, and certain deaths in the disease 
are likewise attributable to toxemia. We have already referred in 
part to the probable mechanism of the characteristic lesions. The 
intestinal necrosis and ulceration are probably due, as we have 
stated, to the occlusion of the blood vessels by proliferated masses 
of endothelial cells, and perhaps both directly and indirectly 
through this hyperplasia, are due to toxins. The parenchymatous 
changes which may occur in heart muscles, liver and kidney are 
likewise attributable to the toxins (Delafield and Prudden). It is 
interesting to note that the nature of the intestinal lesions was 
probably correctly interpreted as eliminative by Sanarelli on the 
basis of animal experiments. This conception seems now almost 
certainly correct in view of our present understanding of typhoid 
fever as a bacteremia and in consideration of further experimental 
evidence with endotoxins, as given by Arima and others. 

A further word might be said in relation to the nature of the 
typhoid toxins themselves. We have already seen that although 
the typhoid bacillus may produce a type of soluble toxin, its 
harmful effects must in large part be attributable to the so-called 
endotoxins. The exact nature of these endotoxins is now in dis- 
pute, as to whether they are specific products of the individual 
race of bacilli or are simply the non-specific poisonous molecular 
group which Vaughan has shown to be present in all proteins, as 
may be shown by their chemical cleavage. Vaughan's further 



78 TYPHOID FEVER 

description of the mechanism by which the poison is liberated in 
the body by ferments, especially engendered during the incuba- 
tion period, seems almost certainly the correct explanation not 
only of the mechanism of fever but of all effects in the disease due 
to toxin liberation. It is further supplemented by the work of 
Friedberger and his collaborators along the same lines in explain- 
ing the nature of anaphylatoxin formation. A more extensive 
discussion of this subject would lead us too far afield, and we will 
refer interested readers to the chapters in Zinsser's " Infection and 
Resistance," which deal with these problems in an authoritative 
manner,* and content ourselves with his admirable summary: f 
"The present status of the question, it seems to us, may be summed 
up as follows: It may probably be accepted as a fact that ana- 
phylatoxin production occurs and accounts for toxemia, altogether 
or in part, in all diseases in which bacteria invade the tissues or 
circulation; in addition to this, soluble toxins produced by the. 
bacteria still living and uninjured may add a further specific ele- 
ment to the condition — in some diseases; whether or not specific 
preformed endotoxins participate in the production of bacterial 
toxemia cannot be definitely stated. It is not, however, a neces- 
sary assumption." 

THE COMPLICATIONS IN TYPHOID 

At this point it may be well to consider in a general way certain 
of the complications of typhoid fever, although reference has been 
made incidentally to certain of them in attempting to describe 
the mechanism of the course of the disease itself. Certain of these 
complications might properly be classed under the sequels which 
will be treated in a following chapter, although an effort has been 
made at a somewhat arbitrary separation of the two on the basis 
that complications occur during the course of the disease or im- 
mediately following it, whereas sequels occur at a somewhat 
more remote period subsequent to recovery from the malady. 
As we have already mentioned, typhoid fever is characterized by 
a high percentage of complications, perhaps in from twenty-five 
to thirty per cent of all cases (Cummings and Brown; Noblecourt 
and Peyre). Their significance is most striking when we consider 
them as causes of death, and we find very definite statements as 
to the relative importance of complications and of the typhoid 
process itself in this respect. Curschmann has estimated that 
the typhoid infection per se, or the severity of intoxication, as he 

* Loc. cit., Chapters II and XVII. t Loc. cit., p. 422. 



THE PATHOGENESIS OF TYPHOID FEVER 79 

calls it, which is equivalent to the word toxemia as used by other 
writers, is the greatest single cause of death, producing from thirty 
to fifty per cent of the fatal cases. This estimate, based on his 
own cases, is probably excessive, or at least does not thoroughly 
represent more modern conditions where we recognize that typhoid 
is a somewhat less virulent disease. Whipple states that the com- 
plications of typhoid are responsible for two-thirds of the fatal 
cases. Dopfer and Holscher agree singularly well in attributing 
fatalities to complications in 75.5 per cent and seventy-six per 
cent, respectively. At any rate, it seems safe to state that the 
majority of deaths in this disease are due to its complications. 

The deaths from the severity of the typhoid infection itself 
are in a general way due to one of three causes, either to the 
hyperpyrexia or to the effect of the toxins of the typhoid bacillus 
on the central nervous system, or, again, to its action on the cir- 
culatory system, affecting, as it does, the heart muscle and the 
blood vessels. In all instances the result is attributable to toxins 
from the typhoid bacillus, the potency of which in turn is, partly 
at least, referable to the actual number of organisms, and partly 
to the virulence of the infecting strain itself. It must be admitted 
that reference to the toxins of the typhoid bacillus, as will appear 
from previous chapters, is not strictly speaking a very exact one, 
since we have very little precise information as to the nature of 
these poisonous substances. In general it may be said, however, 
that severe and fatal cases of typhoid are accompanied, at least 
in their later stages, by a high bacterial count in the circulating 
blood. At this point may be mentioned the sudden deaths in 
typhoid, usually without definitely known causation. Vincent 
and Muratet estimate them to occur in one to three per cent of 
cases. 

Important complications of typhoid fever may be listed cate- 
gorically and more or less in the order of frequency of their oc- 
currence as follows: relapse, hemorrhage, perforation, pneumonia, 
nephritis, laryngitis and necrosis of the larynx, pleurisy, cholecysti- 
tis possibly accompanied by perforation, parotitis, meningitis, 
appendicitis, thrombosis, abscess and pyemia, gangrene and 
splenic abscess. Certain of these complications are worthy of a 
more detailed consideration as throwing light on the actual mech- 
anism of the disease. 

Hemorrhage and Perforation 

Hemorrhage and perforation may be considered together inas- 
much as they are more or less due to the same set of operative 



80 TYPHOID FEVER 

causes. These characteristic and important complications of 
typhoid bear no definite relation to the severity of the disease 
itself, but are obviously accidental and due entirely to mechanical 
causes. They may occur in the mildest cases, and, indeed, are 
very likely to occur in those cases which are so mild as to be am- 
bulatory, thereby giving ample opportunity for greater strain. 
We have already mentioned the explanation which Mallory would 
give as underlying necrosis and ulceration of Peyer's patches, 
which in turn is the underlying cause of both hemorrhage and 
perforation. Mallory's explanation of the extensive necrosis 
which may occur is that it is brought about by mechanical ob- 
struction of the blood vessels through proliferation of the endo- 
thelial cells, which, as he has definitely shown, characteristically 
proliferate in the course of the disease. Another mechanical 
factor of great importance in hemorrhage and which apparently 
has not been sufficiently recognized, is the actual blood supply of 
Peyer's patches themselves. Professor Herbert M. Evans, who 
has made a particular investigation by special injection methods 
of the pattern of the blood supply of the human intestine, has been 
kind enough to furnish me with a statement of his as yet unre- 
ported studies as follows. 

"The particularly disastrous nature of the hemorrhage due to 
erosion of the Peyer's patches (agminated follicles) may find its 
simplest explanation in the peculiar anatomical arrangement of 
the local blood supply. Indeed, the arrangement of the blood 
vessels in the neighborhood of an agminated follicle is so altogether 
peculiar that an injection of the arterioles alone in such an area, and 
any subsequent treatment which renders transparent the bowel 
wall, would enable us to predicate positively the exact position of 
the patch of Peyer. This is due to the fact that the tiny special 
arterioles of the Peyer's patch leave their various places of origin 
from the main submucosal plexus when still some little distance 
from the margins of the patch and pursue an almost unbranched 
course to the patch. There are great numbers of these tiny straight 
coursing arterioles which thus radiate from all sides into the patch 
running almost parallel courses and so frequent that a considerable 
number exist in the length of a centimeter or two. Thus erosion 
near the margins of the patch would easily open up a far greater 
number of arterial sources for hemorrhage than in any other like 
area of the bowel." 

Numerous figures are available in the clinical literature as to the 
frequency of occurrence of these two important complications of 
typhoid, but it is important here to give simply an average of such 






THE PATHOGENESIS OF TYPHOID FEVER 81 

figures which do not vary to an extraordinary degree among 
themselves. As regards perforation, it may be assumed on the 
basis of numerous figures that it occurs in three or four per cent 
of all cases. As a cause of death, however, the percentage referable 
to this unfortunate complication is distinctly higher. Murchison 
estimates that 11.38 per cent of all the deaths in typhoid fever are 
due to perforation, whereas McCrae would attribute twenty per 
cent of the deaths to this cause. Curschmann's figures lie between 
the two, being from fourteen to nineteen per cent. 

Hemorrhage occurs, according to Homolle, who studied the 
reports from ten thousand cases in this respect, in 4.65 per cent 
of all cases. The general average from other writers would lie 
between five and ten per cent, although in certain groups as high 
as thirty per cent of the cases have shown hemorrhage (Whitting- 
ton). Hemorrhage, therefore, is distinctly a more frequent occur- 
rence than perforation, as might be expected, owing to the more 
superficial level of ulceration required to bring it about. But, on 
the other hand, hemorrhage is likely to be a less serious manifesta- 
tion than perforation, for it is the cause of death, according to 
Curschmann, in only six to nine per cent of the cases of typhoid. 
It is interesting to note in this connection the observations of Hare 
and Beardsley, which have led them to state that hemorrhage when 
not fatal will not only not be an unfortunate symptom, but even a 
beneficial one. The mechanism of the benefit produced by hem- 
orrhage is by no means certain, but the suggestion may possibly 
be made that it might be due to the hyperleucocytosis which 
frequently accompanies this complication, and which, as we shall 
see more in detail when we consider the specific treatment of the 
disease, is of distinct beneficial effect. 

Relapses 

The most interesting complications of typhoid infection are the 
relapses. The true relapse of typhoid fever must be distinguished 
from the spurious relapse or recrudescence which mean simply a 
temporary rise in the fever during the descending temperature 
period. The true relapse occurs after an interval of several days' 
normal temperature, that is to say, after the disease, as indicated 
by the fever, has terminated. This interval may be prolonged 
from a few days to four or five weeks of apparent normal con- 
valescence and recovery. The relapse itself is practically a repeti- 
tion of the original disease, although in ordinary course it is usually 
shorter and less serious. The mortality in relapses is low, according 
to McCrae something like 2.9 per cent, and according to Cursch- 



82 TYPHOID FEVER 

mann a little under five per cent. Relapses usually run a shorter 
course than the original disease, frequently of only a few days. 
Many or all of the original symptoms and diagnostic signs of the 
preliminary attack of typhoid fever occur in the relapses. The 
rose spots may reappear (Bartlett) , a new crop of intestinal lesions 
may occur (Adami and McCrae), and as a rule the typhoid bacillus 
is present in the blood, although cultures just preceding this 
period may have been sterile for a number of days. A number of 
relapses may occur; as many as four or five have been recorded. 
The percentage of cases in which relapses have been found varies 
considerably; Murchison had three per cent in his cases, whereas 
Stertzing had over thirteen per cent in a more recent group. Ac- 
cording to Vincent and Muratet, they are particularly prevalent 
in the so-called abortive form of typhoid, the fever of short dura- 
tion, about which more will be said later in connection with ty- 
phoid in the vaccinated and in connection with specific treatment. 

Relapses are undoubtedly due to the overflowing of typhoid 
bacilli from their localized metastatic or ultimate foci in the body, 
which have already been discussed in detail. The particular 
localization in respect to relapse has been attributed by different 
writers to different places in the body; thus v. Futterer and Chiari 
would attribute them to a persistence of the microorganisms in the 
gall bladder, a suggestion which must, at least in part, be true, and 
which was more crudely expressed in pre-bacteriological days by 
Moore, who thought them due to re-absorption of infectious mate- 
rial from the bowel, which will perhaps mean nothing more than a 
re-entrance of typhoid bacilli that have been discharged from the 
gall bladder through the intestinal wall. Stertzing regards the 
persistence of an enlarged spleen as prognostically indicative of an 
oncoming relapse, which would indicate that the foci of bacteria in 
this particular organ give rise to the subsequent overflowing into 
the circulation. Another characteristic sign that has been noted 
by this author is the persistence of the leucopenia, which would 
seem, however, to indicate the bone marrow as the source of re- 
infection, a locality rendered still more likely in view of the ob- 
servations that we have already cited in respect to this tissue. 

A word may be said in reference to the occurrence of pneumonia 
as a complication of typhoid fever. It apparently occurs in from 
ten to fifteen per cent of all cases and may either be of the lobular 
or the lobar type. There are several predisposing factors in typhoid 
which would lead to the ready occurrence of pneumonia, such as 
the initial bronchitis which, as already mentioned, is a common 
symptom, the feebleness of respiration and circulation and the 






THE PATHOGENESIS OF TYPHOID FEVER 83 

recumbent position which leads to a settling of blood in the de- 
pendent parts of the lung. The pneumonia when it does occur 
may be due either to the typhoid bacillus or to an intercurrent 
infection from one of the various types of pneumococci. This 
complication may occur early or late in the disease. 

EXPERIMENTAL TYPHOID FEVER IN ANIMALS 

The complete experimental verification of the typhoid bacillus 
as the true etiological agent in typhoid fever was delayed for many 
years after its isolation, owing to repeated failures to produce the 
analogous syndrome in laboratory animals, as would be required in 
complete fulfilment of Koch's celebrated postulates. We know 
now that this particular postulate may be expected to fail of 
verification in many of the exclusively human diseases, or at least 
can be verified only in anthropoid apes. 

A survey of the attempts to produce typhoid fever in the lower 
animals, both in pre-bacteriological days and subsequent to the 
discovery of the typhoid bacillus, need not detain us long. Non- 
specific congestions of the intestine were induced in animals by 
Magendie (1823) and others following the intravenous injection of 
putrid substances. Similar results, based on the conception of 
typhoid fever as a non-specific spontaneous putrefactive disease 
were obtained by D'Arcet and others. Murchison 3 fed a pig for 
six weeks on the dejecta from typhoid cases, and at autopsy found 
the animal fat and with normal intestines. 

We have already referred in the first chapter to the early exper- 
imental work of Klebs, who claims to have produced a hemor- 
rhagic infiltration without ulceration in the cecum of rabbits by 
means of cultures of the typhoid bacillus grown on gelatine. 
GafTky, as we know, was unable with his more certainly pure cul- 
tures of the bacillus to obtain such results when the organism was 
given either by the mouth or by intravenous injection. Fraenkel 
and Simmonds, 2, 3 by giving large amounts of pure cultures of the 
typhoid bacillus to mice, produced rapidly fatal symptoms with 
swelling and ulceration of the follicles of the small and large 
intestine, together with less definite lesions of the liver, kidney 
and spleen. They very properly, however, did not regard their 
results as similar to typhoid fever in man. It was later shown by 
the work of Sirotinin and by Brieger, Kitasato and Wassermann 
that results of this sort are due to the toxins of the bacillus, and 
similar results can be produced by preparations of these toxins 
from which the bacteria have been removed. In none of these 



84 TYPHOID FEVER 

experiments that have been quoted do the observers claim to have 
produced in animals a disease with a course resembling that seen 
in human typhoid. Sanarelli injected sterilized cultures of Bacillus 
coli intraperitoneally at the same time that the typhoid bacillus was 
introduced subcutaneously. This led to a typhoid culture of ex- 
alted virulence, which in small amounts produced infiltration of 
Peyer's patches which were found to contain typhoid bacilli, as did 
the mesenteric glands and the spleen. Remlinger found that by 
prolonged feeding of rats and rabbits on vegetables soaked in 
water containing typhoid bacilli he was able to induce a con- 
tinued fever, lasting from ten to twelve days, accompanied by 
diarrhea, loss of appetite and wasting. Four of eight rabbits expei- 
imented on became sick. One was killed on the twelfth day and 
one died on the twelfth day of fever. Three or four gave positive 
agglutination reactions, and autopsies on two rabbits showed 
swelling of spleen, lymph glands and Peyer's patches. Similar 
results were obtained by Atlassoff, who obtained intestinal lesions 
in young rabbits resembling those of human typhoid by feeding 
them with pure cultures of the microorganism, or, more partic- 
ularly, with such cultures mixed with certain strains of torula. 
Reference should here again be made also to the work of ob- 
servers like Arima, who produced swelling and hemorrhage of the 
agminated follicles in rabbits by the injection of endotoxins from 
the typhoid bacillus, which observations we personally have been 
able to confirm. We may also refer to the rabbit carrier condition 
which we have already discussed, and which we shall use as illus- 
trative of the human carrier condition in a succeeding chapter. 
This condition, as we have previously pointed out (Gay and Clay- 
pole ] )> resembles in many respects human typhoid fever, omitting 
the stage of infection through the intestine and the intestinal 
lesions which usually accompany the human disease. When 
certain strains of typhoid bacilli are injected into the circulation 
of rabbits, the animal continues to excrete them through the gall 
bladder for long periods of time. The organisms are found at first 
in practically any organ of the body and in the circulating blood, 
but soon disappear from the blood and most of the tissues, with 
the exception of the bone marrow and the gall bladder. The 
agglutinins rapidly rise in the circulating blood as the number of 
microorganisms diminishes. These carrier rabbits usually undergo 
progressive emaciation until death, which takes place in two or 
three months. Fever does not in our experience accompany the 
rabbit syndrome. Such experiments, taken in conjunction with 
the ones we have already mentioned, would seem to show that 



THE PATHOGENESIS OF TYPHOID FEVER 85 

many of the characteristics of human typhoid infection can be 
reproduced in rabbits, although it would be incorrect in all prob- 
ability, in spite of the results of Remlinger and Atlassoff, to claim 
that true typhoid fever can be produced in these animals. 

Attempts made to produce typhoid fever in monkeys or the 
higher apes, were not successful until recently. Sutton as early 
as 1883 had called attention to a disease in three monkeys which 
he regarded as identical with human typhoid fever. The descrip- 
tion of the disease and autopsy findings in two lemurs that died a 
week apart in the same cage after suffering from profuse diarrhea 
seems very circumstantial. In one animal death was due to per- 
foration and at autopsy extensive ulcerations of the follicles were 
found adjacent to the ileocecal valve. Hemorrhage led to the 
death of the second animal, which showed similar lesions extend- 
ing through the cecum. In 1904 Griinbaum attempted to infect 
chimpanzees by feeding them with pure cultures of the typhoid 
bacillus and with stools from typhoid patients. His results, how- 
ever, were at best only suggestive. In 1911 Metschnikoff and 
Besredka, 1 after vain attempts along the line of Griinbaum's 
experiments, succeeded in producing a syndrome in the higher apes 
that must be accepted as essentially similar to the typhoid fever 
of man. Their experiments were undertaken primarily for the 
purpose of testing the efficacy of certain methods of antityphoid 
vaccination and also with the possibility in mind that typhoid 
fever might conceivably be produced not by the typhoid bacillus 
but by some filtrable virus adhering to it, as had been proved to be 
the case in a somewhat similar disease, hog-cholera. Metschnikoff 
and Besredka failed at first to infect chimpanzees with pure cul- 
tures of the typhoid bacillus, but on feeding them with stools from 
typhoid cases they were able finally to produce in these animals a 
characteristic fever accompanied by diarrhea and positive blood 
cultures and Widal. The filtrates of stools as well as killed cul- 
tures of the typhoid bacillus failed to produce this disease. They 
then employed cultures isolated from chimpanzees that had been 
infected in this manner, and found that such cultures would then 
succeed perfectly in reproducing the disease in other chimpanzees. 
They succeeded, indeed, in fifteen out of sixteen instances, and 
their single failure is in itself interesting as offering definite anal- 
ogies to normal human carriers. They succeeded, then, in the 
majority of cases in producing a characteristic fever and three 
deaths due to the infection itself. In all instances the Widal re- 
action was positive in these animals as well as the blood culture. 
Diarrhea was a regular symptom and at autopsy the mesenteric 



86 TYPHOID FEVER 

lymph nodes were enlarged and Peyer's patches hypertrophied, 
although they were not ulcerated. The spleen was in no case 
notably increased in size. They subsequently succeeded in pro- 
ducing a somewhat similar disease in two Macacus monkeys out 
of over fifty that were tried. 

These experiments, then, of Besredka and Metschnikoff fulfil 
completely the last of Koch's postulates, which prescribes that a 
microorganism to be regarded as the causative agent in any given 
disease must be able, when inoculated in pure culture in laboratory 
animals, to initiate the same disease from which it was obtained. 



CHAPTER VI 
THE DIAGNOSIS OF TYPHOID FEVER 

An early diagnosis in each suspected case of typhoid fever is 
important, not only for the welfare of the patient but for the good 
of the community at large. If the case proves to be typhoid, it is 
imperative for the good of the patient that he should be kept in 
bed and properly nursed, and that his diet and treatment should 
be intelligently regulated. The extension of the disease to others 
may, when its nature is recognized, be absolutely prevented. The 
accuracy of purely bed-side diagnosis in typhoid is, in the hands 
of the experienced, considerable. Such accuracy, however, is 
more particularly true of cases in retrospect; an early clinical 
diagnosis can never be made with certainty. The diagnosis of 
typhoid on a clinical basis depends, as in other diseases, on a process 
of symptom-matching; whereas no single symptom of the disease 
is in itself pathognomonic, the group of symptoms is in general 
characteristic. 

The characteristic clinical symptoms of typhoid fever have 
been briefly outlined in the previous chapter. Their detailed 
discussion and their comparison with the symptom complex of 
other diseases affords the material of which clinical treatises are 
made. Such discussion is neither germane to, nor primarily help- 
ful in this attempt to develop a mechanistic conception of typhoid 
fever. No modern physician should wish, or be obliged to make 
a diagnosis of typhoid fever without laboratory aid, and it is 
doubtful if he would ever be justified in arriving at a positive diag- 
nosis when a complete series of laboratory examinations fails to 
confirm his clinical opinion. Clinical suspicion of typhoid is, 
however, the necessary incentive to laboratory diagnostic tests 
and the suggestive symptoms which lead to such suspicion should, 
therefore, be sketched. 

Any fever lasting over a period of days, accompanied by malaise, 
headache, insomnia, and diarrhea, ushered in by chill or nose- 
bleed, particularly when unaccompanied by definitely localizing 
symptoms, except possibly pain on epigastric pressure or sore 
throat, may be suspected of being typhoid fever. If the fever 
is at first marked by afternoon exacerbations with gradual rise, 

87 



88 TYPHOID FEVER 

and is followed in a few days by a more continuous fever, with 
persistent abdominal symptoms and a stuporous condition, if 
the spleen becomes palpable and rose spots appear, the diagnosis 
becomes more assured. A recent history of excursions away from 
home, contact with known cases of the disease, and no history 
of a previous attack of typhoid aids in determining the diagnosis. 
Although the diagnosis on symptomatic grounds is relatively 
easy in certain cases, it may be very difficult in others, owing to a 
suppression or diminution of any or most of the cardinal symp- 
toms, or, on the other hand, owing to the predominance of certain 
secondary symptoms, such as acute cholecystitis, bronchitis, 
otitis media, and the like. 

As already mentioned, typhoid fever may easily be overlooked 
in the beginning and in mild or abortive cases, particularly in 
children. It may readily be mistaken for other acute infections, 
as, for example, influenza, typhus, acute articular rheumatism, 
acute endocarditis, malaria, in proper localities for Malta fever 
or for relapsing fever, and for certain forms of tuberculosis. 

Without futher emphasis on the purely clinical aspects of typhoid 
we may proceed to the methods of laboratory procedure without 
which no diagnosis should be made and in the absence of which 
no certain positive diagnosis can be asserted. We may go even 
further and state that if repeated and complete laboratory tests 
for typhoid fever, properly performed, result negatively, no def- 
inite positive diagnosis of typhoid fever should be made on the 
basis of the clinical examination alone. 

The laboratory diagnosis of typhoid fever is made in one of two 
general ways: by detection of the typhoid bacillus in the body of 
the patient, or by determination of specific reactions produced 
in the body as a result of the infection. 

DETECTION OF THE TYPHOID BACILLUS IN THE BODY 

We have discussed the distribution of the typhoid bacillus in 
the body during the course of the fever to which it gives rise in 
considerable detail in the preceding chapter. We have seen that 
its distribution is general, that it may be found in the mouth, 
throughout the gastro-intestinal tract, in the urine, in the lym- 
phatic system, in the gall bladder, and in all parts of the body 
reached directly or indirectly by the blood stream, which serves 
to disseminate it. The microorganism occurs, moreover, in the 
various complications of the disease, such as pneumonia and 
abscess formation, which it produces alone or in conjunction with 



THE DIAGNOSIS OF TYPHOID FEVER 89 

other bacteria. The typhoid bacillus may, then, at some period 
in the course of the disease be found in practically any given part 
of the body, but, as we have seen, its localization varies to some 
extent during the evolution of the disease. There are, as we have 
noted, certain foci of predilection for the typhoid bacillus, the bone 
marrow, bile, blood, and general lymphatic system in particular, 
in which places the bacteria are not only more constantly present 
but present in larger numbers. Success in detecting the typhoid 
bacillus depends, then, on choosing material that contains the 
micro-organism in con iderable numbers and that is easily ob- 
tained. Typhoid bacilli are most readily isolated from the blood, 
bile, feces, or urine, and the reliability of each of these sources 
varies in accordance with the stage of the disease and with the 
individual case. Success further depends in large measure on the 
technic employed. 

Isolation of the Bacillus from the Blood 

We have indicated the difficulties that were met with by the 
early observers in obtaining positive cultures of the typhoid 
bacillus from the blood. The early failures were due in part to 
the fact that very small amounts of blood were used, frequently 
taken from the tissues surrounding a rose spot, and that small 
quantities of media or unsuitable media were employed. With 
more modern methods it appears that blood cultures are positive 
in approximately seventy-five per cent of all typhoid cases, success 
depending to a considerable extent on the period in the course of 
the disease at which the cultures are taken. 

Blood for cultures is usually obtained from one of the veins 
just below the elbow joint, preferably from the median basilic, 
an engorgement of the vessel having been produced by a tourniquet 
applied to the lower part of the upper arm. In children or obese 
persons it may be very difficult to find this vessel, in which case 
blood may be obtained from the internal saphenous vein as it 
crosses over the internal malleolus, or in the case of children from 
the external jugular. In adults it may be necessary to dissect 
down on the vessel of the arm under local anaesthesia, in order to 
obtain a culture. The area through which the puncture is to be 
made is carefully sterilized, either by scrubbing with soap and 
water followed by bichloride and alcohol, or simply by the applica- 
tion of tincture of iodine, which prepares the skin rapidly and 
completely. In very sensitive individuals it may be wise to in- 
filtrate the subcutaneous tissue with novocaine before inserting 
the needle. The blood is removed by means of a sterile, graduated 



90 TYPHOID FEVER 

glass syringe, preferably of from ten or twenty cubic centimeters 
volume, and fitted with a needle of about eighteen gauge. 

A great deal of the success in obtaining positive blood cultures 
depends on the amount of blood employed. In severe cases where 
the organisms are present in large numbers in the circulation, a 
few drops of blood may suffice to give positive results, but the 
majority of modern observers employ considerable amounts, 
usually ten cubic centimeters. The needle is inserted in the direc- 
tion of the venous circulation, and with gentle suction a sufficient 
amount of blood is readily withdrawn in a few seconds, if the vein 
has been properly entered. Liberation of the tourniquet and 
withdrawal of the needle usually leaves little or no leakage about 
the skin puncture, which should be covered for a few minutes with 
a sterile sponge, or, if desired, protected from the air by a collodion 
dressing. 

Cultures are preferably made at the bed-side, the needle and 
the mouth of the flask containing the media being thoroughly 
flamed over an alcohol lamp before inoculation. There is ample 
time to make successful cultures before coagulation of the blood, 
but if for some reason it is desired to carry the blood to the labora- 
tory before inoculating media, calcium oxylate or a citrate solution 
may be added in sufficient amounts by filling the syringe partially 
with one or the other solution before taking the blood. 

Either solid or liquid media may be employed in making blood 
cultures, the latter being under usual conditions preferable, with 
the exception of those cases in which it is desired to obtain a 
quantitative estimate of the number of bacteria to the cubic centi- 
meter of blood. Solid media also have the advantage of economy 
of material and space, which in diagnosis in the field during war, 
and under similar imperfect laboratory conditions, may be a 
matter of importance. The use of poured plates of a mixture of 
agar and blood was first suggested by Schottmuller in 1900, 2 and 
they are still used, not only for the quantitative purpose just 
mentioned, but also for rapid differential diagnosis between ty- 
phoid and paratyphoid infections. For example, Koenigsfeld has 
recently recommended the addition of one cubic centimeter of 
blood to a slant agar tube containing Endo or Drigalski medium, 
in the latter case employing mannite instead of the usual lactose. 
Bile is added just before this medium is employed. Koenigsfeld 
obtained a high percentage of positive results and has been corrob- 
orated by Schurmann, who has somewhat modified the culture 
tube employed. 

The majority of observers prefer to use a liquid medium, usually 



THE DIAGNOSIS OF TYPHOID FEVER 91 

alkaline bouillon or peptone water. Best results are obtained by- 
using relatively large amounts of blood, usually ten cubic centi- 
meters and about two hundred cubic centimeters of media in an 
Erlenmeyer or Florence flask. This considerable dilution of the 
blood prevents coagulation and checks the bacteriolytic activity 
of the serum, as was first demonstrated by Castellani 2 in 1899. 
Coagulation may also be prevented by the use of citrate solution, 
or better still, by the common method of adding bile, which not 
only prevents coagulation but is a selective medium for the typhoid 
bacillus. 

The value of bile in cultures from typhoid cases was first pointed 
out by Conradi, who used a mixture of pure bile and glycerine 
and added small amounts of blood. This method was perfected 
by Kayser, who omitted the glycerine and used two and one-half 
cubic centimeters of blood to five cubic centimeters of sterile bile. 
This method, in addition to the advantage of using small amounts 
of blood, apparently gives a very high percentage of positive re- 
sults, to judge from the numerous references cited by Kutscher. 
The diagnostic result, however, is arrived at less rapidly than 
when large amounts of liquid media are employed. Streaks are 
made on lactose, litmus agar two or three days after the growth 
in bile, and the organisms then carried further for final identifica- 
tion. According to LeBoeuf and Braun, sterile urine may be used 
in place of bile with equal success. 

The culture method which we personally prefer and which is 
most generally employed consists in the addition of ten cubic 
centimeters of blood to two hundred cubic centimeters of ten per 
cent bile bouillon. Positive results run high, as we shall presently 
discuss, and in the majority of instances smears made from such 
a culture on the following day show Gram-negative bacilli in the 
positive cases. A not inconsiderable number of cases, however, 
will show no organisms for two or even three or four days. The 
diagnosis may be obtained more rapidly by making smears on 
agar from the bile bouillon after its incubation for from six to 
twelve hours. 

Whereas the bile broth cultures or the pure bile methods are 
most certain for eventual diagnosis and in detecting the smallest 
number of bacteria, it is frequently desirable to estimate the 
number of organisms present in a given volume of blood, par- 
ticularly in severe cases, where they are numerous. In this case 
solid media must be employed, and cultures obtained by mixing 
melted agar with a measured amount of blood. In the majority 
of cases it is difficult to obtain sufficient colonies with one or even 



92 TYPHOID FEVER 

two cubic centimeters of blood if a single plate is made. In severe 
cases, however, a considerable number may be obtained from this 
volume. Landsberger has found as many as one hundred colonies 
in two cubic centimeters in the severe and hopeless cases. Both 
Jochmann and Schottmuller have used this method as indicative 
of the prognosis, and we have employed it to a limited extent in 
estimating the effect of vaccine therapy. We have further found 
that cultures from the blood clot are advantageous in estimating 
the number of organisms in a given amount of blood. By using a 
weighed amount of clot, which is then ground with bouillon in a 
sterile mortar, variations in the number of bacteria may be deter- 
mined from day to day. Cultures from blood clots were first 
suggested by Fornet in 1906 and subsequently by Muller and 
Graef and by LeBoeuf and Braun. This clot method has the addi- 
tional advantage of requiring only small amounts of blood, of 
obviating the necessity of immediate cultures at the bed-side, and 
of yielding serum which can be utilized for agglutination tests. 
Blood cultures in cases of typhoid are rarely contaminated 
when properly taken, and only in the very exceptional instances 
of mixed paratyphoid-typhoid infection do they show the pres- 
ence of more than a single organism. The presence of Gram- 
negative, actively motile bacilli in the culture from a suspected 
case is presumptive evidence of typhoid or paratyphoid fever, but 
no diagnosis is complete until the organism has been isolated in 
pure culture and identified by cultural methods and agglutination 
tests. It should be noted in this connection that freshly isolated 
strains of the typhoid bacillus at times fail to respond charac- 
teristically to an antityphoid serum until they have been sub- 
cultured on artificial media. 

The demonstration of the typhoid bacillus in the circulating 
blood is the most convincing evidence of typhoid fever and is free 
from even the few possible exceptions that must be made in draw- 
ing conclusions from the agglutination test. In addition, blood 
cultures are positive in nearly as high a percentage of cases as the 
agglutination test. Blood cultures have the further great ad- 
vantage of being most frequently positive in the first week of the 
disease, at which time the Widal test is frequently negative. In 
view of the importance of early diagnosis, this fact is of great 
significance. The relative percentages of positive results from 
blood cultures have naturally varied markedly in the evolution of 
the methods which we have endeavored to outline. One hundred 
per cent of positive results, not only in the first week but at any 
time during the course of the disease, has been claimed by some 



THE DIAGNOSIS OF TYPHOID FEVER 93 

observers in a limited number of cases. It is certain, however, that 
on the average no such perfect success can be expected. In the 
following tables (Tables VII and VIII) we summarize considerable 
and recent statistics which show the results that may be expected 
from blood cultures at different stages in the course of typhoid 
fever. The data of Coleman and Buxton in these tables sum- 
marize the results in 1602 cultures based on the entire available 
literature and their personal experience. Our own results, as well 
as those of Mann, Rainsford and Warren, are based entirely on 
personal observations. 

TABLE VII 

PERCENTAGE OF POSITIVE BLOOD CULTURES IN CASES OF TYPHOID FEVER 







Per Cent Per Cent on 






Positive Repeated Cultures 


Coleman & Buxton 






collected results 


1602 cultures 


75% - 


Mann, Rainsford & 






Warren 


391 cases 


77% - 


Gay 


98 " 


71% 87% 



TABLE VIII 

PERCENTAGE OF POSITIVE CULTURES IN RELATION TO TIME OF DISEASE 





1st wk. 


2dwk. 


3d wk. 


4th wk. 


After 4th wk. 


Coleman & Buxton 


89 


73 


60 


38 


26 


Mann, Rainsford & 












Warren 


80 


62 


50 


36 


— 


Gay 


73 


80 


53 


40 


33 



It will be seen from Table VII that the percentage of positive 
cultures by similar methods differs very little in the hands of these 
three observers. It is not certain whether the results of Mann, 
Rainsford and Warren and of Coleman and Buxton were based 
on repeated examinations in each given case or on a single examina- 
tion, the latter being the probability. We have, therefore, added 
in our own cases the percentage of positive results on initial exam- 
ination and the increased percentage obtained when more than one 
examination was made. The latter figure, of course, represents 
results that should be available in the diagnosis of any given case. 
It is evident, then, that a positive diagnosis may be expected from 
blood cultures in from seventy-five to eighty-five per cent of all 
cases of typhoid fever. 

In Table VIII is found an expression of the experience of prac- 
tically all observers who have taken any considerable number of 



94 TYPHOID FEVER 

cultures in cases of typhoid fever. It will be seen that the number 
of positive cultures diminishes from the first week, or perhaps the 
early part of the second week, as judged from our own figures, 
onward. The high percentage of cultures we obtained in the second 
week may be due to the inevitable uncertainties in estimating the 
day of the disease correctly. In addition to these tables, a number 
of observers have found that blood cultures in the relapses of 
typhoid are usually positive. Coleman and Buxton, for example, 
list cultures from relapses in thirty-three cases, of which ninety per 
cent were positive. Clarke obtained thirty-seven positive cultures 
out of forty-six cases (eighty per cent). 

Whereas cultures are more likely to be positive in the early days 
of typhoid fever, agglutination reactions are more frequently 
positive later in the course of the disease, as we shall see at a later 
point. These facts, which are undoubted, give the impression that 
there must be some relation between the two results. It is con- 
venient and probably correct to think of the course of typhoid 
fever as representing a balance of forces between the invading 
agent and the resisting host. It seems certain that the building up 
of antibodies postulates the disappearance of bacteria and that 
recovery is finally due to their complete destruction, at least in the 
circulating blood. A careful analysis of the strength of the Widal 
which we have estimated in a large number of cases, however, fails 
to show any direct relation between its potency and the presence 
or absence of positive blood cultures. On the other hand, we do 
find with Schtulern that a sudden jump in the Widal titer is usually 
coincident with the disappearance of the bacteremia. This is 
particularly true in cases that have been treated by intravenous 
injections of vaccines, where such an occurrence often takes place 
in conjunction with the characteristic reaction produced by this 
type of therapy. The disappearance of bacteria from the blood 
has also been shown by Ghenken to be coincident with the dis- 
appearance of the Diazo reaction, one of the diagnostic signs in 
typhoid, which we shall consider later. 

Isolation of Bacillus Typhosus from the Stools 

A. Pfeiffer in 1885 showed that typhoid bacilli are present in the 
stools of cases of typhoid fever. We have discussed, in the last 
chapter, the distribution of the typhoid bacillus in the gastro- 
intestinal canal, which affords the channel of entry into the body. 
We know that the original infecting dose of typhoid bacilli is 
absorbed from the intestinal canal into the lymphatic system, but 
the bacillus subsequently reappears in the intestine, owing to its 



THE DIAGNOSIS OF TYPHOID FEVER 95 

elimination in large numbers from the gall bladder. As we have 
already stated, the organism is present in the intestine in largest 
numbers relatively late in the disease and occurs both in larger 
numbers and in greater purity in the upper parts of the intestine. 
In the lower levels it is not only mixed with, but actually in- 
hibited or killed by overgrowth of the colon bacillus. It appears 
also that a carbohydrate diet decreases the number of typhoid 
bacilli and increases the number of colon bacilli. At all events, the 
typhoid bacillus is less readily isolated from the stools than from 
the blood, owing to the admixture of other bacteria. Isolation of 
the bacillus from the stools is not so important a procedure in the 
diagnosis of typhoid fever as it is in the detection of typhoid car- 
riers, and it is chiefly from the latter standpoint that the most 
extensive investigations have been made. 

Typhoid bacilli are more readily found in fluid than in solid 
stools, either during the course of the disease or in convalescence. 
It is usually preferable to dilute the stools and to allow them to 
stand and separate out, subsequently seeking the microorganism 
in the upper and more fluid part. Inasmuch as the organism is 
present in larger numbers in the duodenum, various cathartics 
have been employed to bring down the contents of the upper 
bowel rapidly. Elaterin has recently been employed by Tonney, 
Caldwell and Griffin with great success for this purpose in a series 
of suspected carriers. A very great number of methods and media 
have been described for the isolation of the typhoid bacillus from 
its admixture with other organisms in the feces. The difficulty of 
isolation is increased by the fact that there is, strictly speaking, no 
medium which may be employed for the enrichment of the typhoid 
bacilli at the expense of the other bacteria which are usually 
present in predominating numbers. Schmitz 2 has claimed that 
the addition of beef serum to media will accomplish this purpose. 
The addition of an agglutinating antityphoid serum has been 
used to collect a few typhoid bacilli that may be present in con- 
taminated water, and thereby to facilitate their isolation. In a 
converse manner Landmann has added an anticolon serum to 
dilute stools; after standing and centrifugalization, the super- 
natant fluid is injected into the peritoneal cavity of a guinea pig. 
The exudate, removed thirty minutes later and plated, gives a 
pure culture of Bacillus typhosus. But, in general, the methods of 
isolation depend on the relatively greater resistance of the typhoid 
bacillus to certain harmful substances and on certain minor 
biological peculiarities of its growth. We have already discussed 
the biological properties of Bacillus typhosus, which serve to 



96 TYPHOID FEVER 

differentiate it from Bacillus coli and which may be used, there- 
fore, in the isolation of the specific microorganism. The isolation 
of the specific microorganism may be effected either in one or in 
two stages by means, first, of a preliminary treatment designed to 
inhibit or destroy other organisms, and, secondly, by the plating 
methods which serve to differentiate separate colonies of typhoid 
from other colonies, either directly from the stools or after they 
have been subjected to the preliminary inhibiting treatment. 

The means of inhibiting the growth of other bacteria and thereby 
enhancing the possibilities of finding the typhoid bacillus depend 
on the biological peculiarities that we have already discussed. 
Among these may be mentioned, first of all, the greater motility 
of the typhoid bacillus, a fact which is made use of in the sand 
tube and general filtering methods that have been mentioned. 
More important, however, is the employment of various chemical 
substances which inhibit the growth of streptococci and colon 
bacilli in particular and leave typhoid bacilli relatively unaffected. 
The most important of these are malachite green, brilliant green, 
crystal violet, caffeine, and more recently petrol ether, the action 
of all of which materials we have discussed in detail. 

Typhoid bacilli may be found in the stools with or without 
preliminary treatment by making smears over the surface of pre- 
pared plates. A sterile glass rod is dipped in the fluid and often 
diluted stools and smeared over the surface of a succession of 
plates without re-inoculation. The most important media em- 
ployed in preparing these plates are the Conradi-Drigalski medium, 
containing lactose, litmus, nutrose and crystal violet, and Endo's 
medium, containing lactose, basic fuchsin and sodium sulphite. 
On such surfaces the colonies of typhoid bacilli are differentiated 
from those of colon bacilli by their failure to produce acid. Sus- 
pected non-acid colonies are then tested further on one or more 
of the various differentiating media, such as Russell's medium, 
Congo red, neutral red or subacetate of lead, as well as the or- 
dinary media such as litmus milk and various differential sugars. 
They are then finally tested for their agglutinability by a typhoid 
immune serum. 

The detection of typhoid bacilli in stools depends a great deal 
on the skill of the individual investigator and his employment of 
a medium to which he is accustomed. The percentage of positive 
results, moreover, varies in accordance with the stage of the dis- 
ease, for reasons that we have fully discussed. The microorganism 
may be demonstrated in a very high percentage of cases under 
proper conditions. Klinger, for example, was able in 3214 ex- 



THE DIAGNOSIS OF TYPHOID FEVER 97 

animations to find Bacillus typhosus in eighty-one per cent of all 
cases. Hiss, 2 who was one of the earlier observers, found typhoid 
bacilli in the stools in a little over ten per cent during the first 
ten days of the disease, in fifty per cent from the eleventh to the 
twentieth day, and in over eighty-one per cent from the twenty- 
first day on. Recent comparative results of various investigators 
in obtaining typhoid bacilli, arranged in accordance with the 
week of the disease, are illustrated in Table IX. 

TABLE IX 

PERCENTAGE OF POSITIVE CULTURES FROM STOOLS IN SUCCESSIVE WEEKS OF 
TYPHOID FEVER 

lstwk. Sdwk. Sdwk. 4th wk. Total No. Cases 

Brion & Kayser 32 35 45 144 

Bohne 23 43 100 27 

Gaehtgens & Bruckner 57 53 77 50 100 

Isolation of the Typhoid Bacillus from the Bile 

The early and continued localization of typhoid bacilli in the 
gall bladder and bile has been much insisted on. The constant 
presence of the organism in this locality has suggested the possi- 
bility of its isolation for diagnostic purposes from this source. 
The only difficulty in this method lies in obtaining the bile, and 
this is possible by one of two methods, either by an oil meal or 
by intubation. In the first case 100 to 200 cubic centimeters of 
olive oil are given on an empty stomach, removed from the stomach 
after an hour or two, and found to contain a considerable admix- 
ture of bile. Kiralyfi was able to obtain the typhoid bacillus from 
bile obtained in this manner in cases that failed to show the or- 
ganism in the blood or feces, and a number of other authors (e. g., 
Carnot and Weill-Hall6) have also used this method with some 
success as accessory to feces examination. 

The other and now more usual method of obtaining bile is by 
the use of Einhorn's duodenal sound as employed by Hess as 
early as 1912, which yields within a few hours on aspiration con- 
siderable amounts of pure bile. 

Our own experience with cultures from the bile in a limited 
series of cases leads us to believe with Purjeesz and Stepp that 
cultures are rarely positive when the feces are negative, although 
it unquestionably gives an additional method of diagnosis, par- 
ticularly in the case of carriers, and, apart from the difficulty in 
obtaining material, gives an easier method of isolating the or- 
ganism than from the feces. As examples of the success in mak- 



98 TYPHOID FEVER 

ing bile cultures, it may be noted that Reading obtained thirteen 
positive results out of eighteen in cases of typhoid, and Kaspar 
found typhoid bacilli in the bile seven years after recovery from 
the disease. 

Isolation of Typhoid Bacilli from the Urine 

One of the metastatic foci of typhoid bacilli in the body during 
the course of the disease is the kidneys. Small nodules of bac- 
teria were histologically demonstrated in this locality by Konja- 
jeff in 1889, and had been isolated from the urine by Hiippe 
three years previously. Petruschky in 1898, pointed out the 
importance of the urine from typhoid cases and during conva- 
lescence as a means of spreading the disease. When the organism 
is present, it is relatively easy to detect, owing to the fact that 
it is usually in pure culture. It occurs in twenty-five to fifty per 
cent of all cases, and probably more frequently when albumin is 
present in the urine. Its appearance in the urine is, as in the 
case of the stools, more likely from the second or third week on- 
ward. Enormous numbers of bacteria may be present, as many 
as thirty to one hundred millions to the cubic centimeter. It is 
said to occur coincidently with the appearance of the roseola on 
the surface of the body, which is simply another metastatic focus. 
The presence of the microorganisms in the bladder under usual 
conditions gives rise to no distinctive symptoms, although it may 
lead after convalescence to severe cystitis. 

Among other sources that may be mentioned for obtaining 
typhoid bacilli from the body as a means of diagnosis in typhoid 
fever are splenic pulp obtained by puncture, pus from localized 
complications, the sputum during the disease, and smears from 
the throat and tonsils. These sources are much less reliable 
than the ones that we have discussed more fully, and, in the case 
of the splenic pulp at least, offer so grave a danger in securing 
material as to make it impossible to recommend the method. 

THE DIFFERENTIAL DIAGNOSIS OF BACILLUS TYPHOSUS 

Suspected colonies of typhoid bacilli are taken in subculture 
from blood, stool, urine or bile specimens that have been plated 
or smeared on solid media and further examined. A simple smear 
on agar may be made in the case of blood cultures where the 
growth is obviously a pure one. Such pure cultures are then 
further studied and identified as typhoid bacilli in accordance with 
accepted cultural characteristics and by means of agglutination 



THE DIAGNOSIS OF TYPHOID FEVER 99 

tests. Certain of the preliminary steps in the determination 
are usually made during the process of isolation, particularly 
when selective sugar media serve to separate non-acid-forming 
colonies from colon bacilli. Any organism to be a proved typhoid 
bacillus must fulfil at least the essential characteristic tests, 
which are briefly as follows: 

The organism is a Gram-negative, motile bacillus, which pro- 
duces very slight acid and never coagulation in litmus milk, pro- 
duces acid in glucose media without gas, and no change in lactose 
or saccharose. It produces no indol in peptone water or bouillon 
and no change in neutral red agar. 

In addition to the cultural characteristics, the ultimate and 
necessary proof of an authentic typhoid bacillus lies in its specific 
response to antityphoid serum. A diagnostic serum of this sort 
is produced by the immunization of animals, usually rabbits, 
horses or goats, by repeated injections of one or several authen- 
ticated typhoid strains. The serum of known typhoid cases may 
in some cases be employed in the diagnosis of suspected bacteria. 
An artificial immune serum for diagnostic purposes should be 
able to clump laboratory strains of typhoid in dilutions of one 
to 5,000 or more, and any suspected typhoid bacillus should re- 
spond characteristically up to or very nearly to the titer limit of 
the serum. Difficulty is at times met with, however, in certain 
recently isolated strains of bacilli which fail to respond in a char- 
acteristic manner. This inagglutinability of recently isolated 
strains of the typhoid bacillus, as first noted by McWeeney, is 
of interest in its general bearing on the problem of pathogenicity 
and variations in antigenic properties in a given species. It seems 
undoubted, not only that individual strains of bacteria of a recog- 
nized species differ in their properties of producing disease, but, 
further, that pathogenic properties disappear through the resi- 
dence of a microorganism in artificial culture media. Although 
with many organisms, including the typhoid bacillus, it is not 
possible to demonstrate such loss of pathogenicity since we know 
even old laboratory cultures may produce human infections, 
with certain other bacteria, as, for example, staphylococcus and 
streptococcus, such loss in pathogenicity after isolation from the 
body is very evident. There is, on the other hand, evidence that 
the growth of typhoid bacilli in the body, in immune serum, or on 
blood media renders them more resistant to the action of serum 
and probably to the protective power of the body. Patrick has 
shown that cultures isolated early in the course of the disease 
agglutinate better than those during later stages, and those from 



100 TYPHOID FEVER 

the stools better than organisms obtained from the blood. In 
other words, growth in the blood tends to render the organism 
less susceptible to the action of a specific serum than organisms 
that have been out of the body for some time. Sick has shown 
that typhoid bacilli grown on blood media are less agglutinable. 
In general it has been found that fully virulent typhoid bacilli 
are less agglutinable than avirulent strains (Fornet 2 ). Minor 
variations in agglutinability may be produced by simple varia- 
tions in the culture medium, as, for example, increasing the amount 
of alkali (Wassermann) , or by the use of malachite green (Lentz 
and Tietz). This whole question has been studied by Gay and 
Claypole, 2 owing to an interesting observation made in connec- 
tion with studies on the carrier conditions in rabbits. It was 
found that typhoid bacilli that had been long resident in the 
rabbit body and had been grown outside the body on media con- 
taining rabbit blood became wholly inagglutinable by a strong 
(titer 1 to 20,000) antityphoid serum, produced by immunizing 
rabbits against ordinary stock cultures of the same organism. 
It was found, however, that when a serum was produced by 
immunizing rabbits with blood agar cultures of the same strain 
of the typhoid bacillus, the blood strain was readily agglutinated. 
These observations are not only of theoretical interest but of 
practical importance in the diagnosis of strains of typhoid bacilli. 
Gay and Claypole found that such an antiserum to blood strains 
of typhoid bacilli would agglutinate recently isolated strains of 
typhoid bacilli, which were either only feebly or not at all ag- 
glutinated by the ordinary diagnostic serum. 

DIAGNOSIS OF TYPHOID FEVER BASED ON SPECIFIC REACTIONS ON 
THE PART OF THE PATIENT 

Typhoid infection produces reactions in man which are more 
or less specific, which may be demonstrated by methods of lab- 
oratory precision, and are of great value in diagnosis. These 
reactions may be grouped under four general headings : serum re- 
actions, reactions of localized hypersusceptibility; metabolic reac- 
tions, as demonstrated by certain chemical changes in the body; 
and, finally, reactions on the part of the leucocytes. 

Serum Reactions 

The reactions evidenced by changes in the blood serum are 
among the most characteristic, specific and diagnostically valuable 
signs of typhoid fever. Of these reactions the most important 



THE DIAGNOSIS OF TYPHOID FEVER 101 

is that of agglutination. The phenomenon of agglutination was 
first observed by a number of French investigators, Charrin and 
Roger, Metschnikoff, and Bordet in particular, before its diagnos- 
tic significance, particularly as evidenced in typhoid infections, 
was appreciated. This reaction depends on a specific property 
which appears in the serum of an animal that has been infected 
or artificially immunized against any particular microorganism. 
This property is evidenced by the rapid agglomeration of suspen- 
sions of the causative microorganism produced by addition of the 
specific serum in question, even in minute traces. In the case of 
the typhoid bacillus the utilization of this reaction in diagnosis 
was preceded by observations on the part of Gruber and Durham, 
and by Pfeiffer and Kolle, 2 who commented independently on 
the properties that typhoid immune serum has of immobilizing 
and clumping the typhoid bacillus. The utilization of this fact 
in the diagnosis of typhoid was undoubtedly first appreciated by 
Gninbaum 2 in Nothnagel's clinic, although he failed to record 
his observations until after the publication of a limited series of 
cases by Widal, who had independently obtained the same results. 
This diagnostic method depends on the more or less specific power 
which the serum of typhoid patients has of agglutinating typhoid 
bacilli. 

The methods which are employed in carrying out the agglutina- 
tion test in typhoid have changed remarkably little since Widal's 
description, owing to its relative simplicity. Material from the 
patient may be obtained either by allowing a few drops of blood 
to dry on a glass slide or other impervious surface, or, somewhat 
better, by obtaining a small amount of blood and allowing it to 
clot in a tube, in which case the expressed serum is utilized. Diag- 
nosis by means of serum is distinctly more accurate in point of 
view of dilution used, and the obtaining of serum for this purpose 
sufficiently simple to be expected of the general practitioner. A 
series of dilutions are made either by dissolving the dried blood 
in salt solution or distilled water, or by using a measured amount 
of blood serum; and to each of this series of dilutions, as well as 
to a control tube containing salt solution, is added the same meas- 
ured amount of typhoid bacilli. The typhoid bacilli employed 
may be either in the form of fresh, living bouillon cultures or agar 
cultures freshly suspended in bouillon, or else cultures killed and 
preserved by the addition of formalin (0.1%). The use of living 
cultures is somewhat more general and has the advantage of illus- 
trating the two successive phases in the reaction, namely, a loss 
of motility on the part of the typhoid bacilli and their subsequent 



102 TYHPOID FEVER 

clumping. It has, however, the disadvantage of requiring daily 
preparation, offering dangers of infection, and affording a less 
uniform reagent for the test. The choice between these two prep- 
arations of the typhoid bacillus, again, is somewhat dependent 
on the method by which the dilutions and the reaction in general 
are carried out. There are two general methods that are employed, 
the microscopic and the macroscopic. 

The microscopic method requires smaller quantities of blood 
and is carried out by making dilutions by the drop method with 
the addition of bouillon or salt solution to the serum. Each of 
these dilutions is then mixed with an equal amount of the culture 
or preparation of the typhoid bacillus on a glass coverslip, which 
is inverted and sealed with vaseline over a hollow ground slide. 
Such preparations when observed at intervals soon show a loss 
of motility on the part of the living bacteria and their aggregation 
in small clumps. The reaction should be complete within an hour 
to be diagnostically positive, and frequently occurs in a few min- 
utes. 

The macroscopic method is distinctly more accurate in point 
of view of dilution of the serum, and, therefore, measures the 
actual potency in agglutinins of any given serum. Personally, 
we recommend this method not only for accurate scientific work 
in which it is absolutely necessary, but for diagnostic purposes as 
well. Small amounts of serum are carefully measured either by 
means of a graduated pipette or by the drop method, and usually 
so arranged that the given dilution is available in a volume of 
one cubic centimeter. A series of dilutions of this sort is then 
arranged in test tubes and to each dilution the same amount of 
a living or formalin killed culture is added and the mixture care- 
fully shaken. The result of the test performed in this manner is 
judged by the complete sedimentation of all the bacteria as read 
on the following day, with coincident clarification of the super- 
natant fluid. The macroscopic method is clearly positive or 
negative, and gives no pseudo reactions, such as loss of motility 
with partial clumping, as may confuse the diagnosis when the 
microscopic method is followed. In an extended experience we 
have also found the use of formalin killed cultures of greater deli- 
cacy and accuracy for diagnostic purposes than when living cul- 
tures are employed. 

A standard culture of the typhoid bacillus should be consist- 
ently employed in diagnostic tests. This culture should be chosen 
in accordance with its ready and unvarying agglutinability under 
ordinary conditions of culture. 



THE DIAGNOSIS OF TYPHOID FEVER 103 

Another modification of the agglutination test has been sug- 
gested by Mandelbaum, 2 and depends on the phenomenon of 
agglutination in threads rather than clumps, as previously de- 
scribed by Pfaundler. Mandelbaum found that bouillon cultures 
of the typhoid bacillus, allowed to grow for several hours at 37° 
with admixture of serum from a typhoid patient, tend to grow in 
chains which are characteristic and which do not occur when the 
organism is grown in the serum of non-typhoidal cases. This 
thread reaction of Mandelbaum's has since been obtained by other 
observers (Gaethgens and Kamm; Ast) and found to be somewhat 
more delicate than the ordinary agglutination test in point of 
dilution, and possibly of earlier diagnostic significance. It has 
not, however, been generally adopted. 

The determination of the degree of dilution that is diagnostically 
positive in typhoid is of great importance. Widal originally 
thought the reaction diagnostically positive when present in a 
dilution as low as one to ten. It has since been shown that the 
sera of normal individuals may give such a reaction, at least when 
the microscopic method is followed, and the ordinarily accepted 
standard for a positive reaction is one to forty or one to fifty, at 
which dilution normal serum has been found rarely or never to 
react. From our personal experience with formalinized cultures 
we find that a dilution of one to forty may certainly be accepted as 
positive, and positive reactions of one to twenty or even of one to 
ten are only in the rarest instances present in normal individuals or 
in those suffering from other diseases when the macroscopic 
method is employed. Thus, in sixty-seven non-typhoidal cases 
which we studied in connection with a larger series of proved 
typhoid cases, a positive agglutination test was obtained at a 
dilution of one to ten in only three (4.5 per cent), and in at least 
two of these individuals a previous history of typhoid could cer- 
tainly not be excluded. A dilution, then, of even one to ten is with 
our method very suggestive. The strength of the dilution varies 
considerably in individual cases and during the course of any given 
case. In general, it is found to increase after its initial appearance, 
although it may fluctuate markedly, and at times, after becoming 
positive, disappear. A reaction in a dilution of one to three hun- 
dred or four hundred is in our experience common, and it has been 
obtained as high as in a dilution of one to 163,840 (Kleinberger) . 
We are inclined to attach some significance to the strength of the 
Widal in relation to the prognosis. In general, it would seem that 
a strong Widal indicates a more successful resistance and gives 
better promise of the outcome. It certainly bears some relation 



104 TYPHOID FEVER 

to the results obtained with vaccine therapy, as we shall see in a 
later chapter. 

The agglutination test, whereas highly accurate and valuable 
in the diagnosis of typhoid fever, is by no means absolute. It is 
open to several causes of error which may militate against its 
unequivocal acceptance in any given case. A negative result is 
certainly not proof of the absence of typhoid fever, owing to the 
lateness in the appearance of the reaction in many cases. On the 
other hand, a positive result is highly indicative of typhoid fever, 
with certain exceptions. The most important of these exceptions 
lies in the case of suspected typhoid fever in an individual that had 
been vaccinated against the disease. Such individuals as a result 
of vaccination show agglutinins in their blood serum under or- 
dinary conditions, at least for several months. In such a given 
case the diagnosis of typhoid fever, which may occur in spite of the 
prophylactic treatment, is difficult. We shall discuss it more fully 
in connection with prophylactic immunization, but it may be 
stated here that a positive diagnosis is probable even in these cases 
when an originally positive Widal in low dilutions increases coin- 
cidently with a suspected fever. It has also been claimed by 
Seiffert and by Dawson that vaccination against typhoid does not 
produce a group agglutinin for Bacillus enteriditis (Gaertner), 
whereas the serum of typhoid cases does contain such a minor 
agglutinin. Another possible error in diagnosis lies in the occa- 
sional failure of the test to differentiate between typhoid and 
paratyphoid fevers. The serum of a paratyphoid fever case will 
under certain conditions agglutinate the typhoid bacillus as well as 
the paratyphoid bacillus responsible for the infection. The error 
in diagnosis, although not a serious one, militates against the 
absolute specificity of the reaction. In general, it is found, how- 
ever, that the reverse is more likely to be true; that is to say, the 
serum of a typhoid case may agglutinate the paratyphoid bacillus, 
particularly Paratyphosus alpha, as well as Bacillus typhosus. 
When the Widal is low, say in a dilution of one to fifty, it is possible 
that the typhoid bacillus may be agglutinated in higher dilution 
than the paratyphoid bacillus in a case of paratyphoid fever. 
When, however, the reaction to the typhoid bacillus is high, say 
one to two hundred, it is not likely that the infection is anything 
other than straight typhoid fever. The possibility of a double 
infection due to the typhoid bacillus and one of the paratyphoids 
should be kept in mind. Such infections have been bacteriolog- 
icaliy proven by blood cultures. At all events, the differential 
diagnosis may be possible in anomalous group reactions of this 



THE DIAGNOSIS OF TYPHOID FEVER 105 

sort by utilizing the absorption method of Castellani, which serves 
to differentiate between major and minor agglutinins, and thereby 
to indicate the organism which is really giving rise to the infection 
in question. A description of this method will be found in many 
modern text-books on bacteriology and immunology. 

As indicative of the value of the agglutination reaction in the 
diagnosis of typhoid fever, we present in the following table com- 
parative recent results with the agglutination test. This table 
shows not only the percentage of cases which give a positive 
agglutination test at some time during the course of the disease, 
but also indicates the expectation of positive diagnoses at different 
stages. 

TABLE X 

RECENT ESTIMATES OF POSITIVE AGGLUTINATION REACTIONS IN TYPHOID FEVER 
IN SUCCESSIVE WEEKS 

lstwk. 2d wk. 3d wk. J^ih wk. 5th wk. Average 

Park and Williams 20 60 80 90 88 

Tanaka 70 — 86.4 100 

Gay 61 82 87.5 92 100 91.8 

It is evident from this table that a positive agglutination test 
may be expected in about ninety per cent of all cases, and that the 
success in obtaining a positive result increases very markedly from 
the second week onward, until it is positive in nearly all cases by 
the fourth week. 

A number of other serum tests have been suggested for typhoid 
fever. They are all of interest as indicating the nature and degree 
of the reaction produced in the human body by typhoid infection, 
but none of them approach the agglutination test in reliability for 
diagnostic purposes. They may, therefore, be very briefly sum- 
marized. 

Fixation Reactions in Typhoid 

Typhoid fever was one of the conditions in which Bordet and 
Gengou were able to demonstrate the presence of sensitizing sub- 
stances by means of their now famous reaction of alexin fixation. 
These authors found that if the serum from a convalescent case of 
typhoid fever is mixed with the typhoid bacillus, it acquires a new 
property, due to some change in its colloidal complex, of fixing the 
reactivating substance of fresh serum, known as alexin or comple- 
ment. The occurrence of this reaction in typhoid cases led Widal 
and Le Sourd to test it out as a diagnostic method. They found it 



106 TYPHOID FEVER 

present in fifty-nine out of sixty-one cases, and similar results have 
frequently been obtained by others. There is no question but 
that at some time in the course of the disease a fixation reaction 
may be demonstrated. Its appearance, however, is delayed even 
longer than the agglutination reaction, and it does not ordinarily 
occur before the second or even the third week (Hage and Koriff- 
Petersen). The reaction is most successful when carried out with 
a polyvalent antigen, which again suggests the multiplicity of 
bacterial strains that may be responsible for typhoid fever. Gar- 
bat has recently found that the fixation reaction is not so likely to 
occur following immunization against typhoid as it is during the 
course of typhoid fever. Its presence, therefore, is of some di- 
agnostic value in suspected typhoid fever in vaccinated individuals. 

The Bactericidal Property of the Serum of Typhoid Patients 

Stern and Korte have suggested a test which has been used to a 
limited extent in diagnosis. They found that if the heated serum 
of typhoid cases in very considerable dilution, in some cases as 
great as one to 50,000, is added to a mixture of living typhoid 
bacilli and rabbit alexin and incubated, plates made at intervals 
will subsequently show destruction of the organism. No such 
destruction is produced by the serum of normal individuals or of 
other cases. This reaction is important as indicating an increase 
in bacteriolytic antibodies in the course of typhoid fever, but has 
been found generally of less reliable diagnostic value than the 
agglutination test. 

Tropins and Opsonins in Typhoid Serum 

It may be definitely accepted (Fornet 2 ) that the opsonic index 
or tropin titer of the serum of typhoid cases almost invariably ex- 
ceeds that of normal individuals, reaching frequently 1.5 to 2.5. 
Miss Smith in our laboratory has confirmed this finding. The 
complexity and uncertainty of the technique, however, render this 
test of little value as a diagnostic procedure. 

Among other serum tests which have been suggested in typhoid 
are the demonstration of a typhoid precipitinogen, shown by 
adding a strong antityphoid serum to the serum of a case of ty- 
phoid fever (Fornet 3 ) ; the myostagmin reaction, depending on 
a change in surface tension when an extract of typhoid bacilli is 
mixed with typhoid serum (Ascoli); and the conglutination reac- 
tion (Gay and Lucas). None of these reactions have, however, 
been sufficiently worked with to merit further comment. 



THE DIAGNOSIS OF TYPHOID FEVER 107 



METHODS OF DIAGNOSIS DEPENDING ON EVIDENCE OF LOCALIZED 
HYPERSUSCEPTIBILITY IN THE PATIENT 

Several tests have been proposed in typhoid fever, the success 
of which depends on the demonstration of the hypersusceptibility 
of the patient to the infecting agent. Among these may be men- 
tioned the opthalmo reaction proposed by Chantemesse. This 
reaction is produced by dropping a small amount of fluid con- 
taining one-fiftieth of a milligram of powdered typhoid toxin in 
the conjunctival sac. A much more severe reaction is obtained 
in typhoid cases than in normal individuals. In fact, a sero- 
fibrous exudate is frequently produced. A number of attempts 
have been made to diagnose typhoid fever by the presence of 
a cutaneous or intradermal anaphylactic reaction. Such studies 
have been made by Wolff-Eisner, Link, Floyd and Barker, and 
Jeanneret. Such reactions may be demonstrable late in the course 
of the disease, but, owing to their tardiness in appearance, are 
of no considerable diagnostic value. A similar reaction has, how- 
ever, been found by Gay and Force to occur in recovered typhoid 
cases and serves as an index of immunity to typhoid fever. As- 
coli 2 has demonstrated a passive transfer of hypersusceptibility 
by injecting the serum of typhoid cases in guinea pigs that are 
subsequently given extracts of typhoid bacilli. 

Vincent has described a characteristic reaction in the spleen 
in cases of typhoid fever, when the individual is given an injection 
of two cubic centimeters of autolysate obtained from typhoid 
bacilli. In response to such an injection, the spleen of the ty- 
phoid case may be demonstrably increased in size in from twelve 
to eighteen hours after inoculation. 

DIAGNOSTIC REACTIONS DEPENDENT ON CHANGED METABOLISM 
IN TYPHOID FEVER 

The prolonged course of typhoid fever is accompanied by marked 
destruction of the body proteins. This destruction is demon- 
strable in the patient's urine. During the febrile height of the 
disease the urine is decreased in amount, frequently contains 
albumin, and usually shows an increase of urea and uric acid, 
and a diminution in chlorides. Indican is present in large amounts 
and the toxicity of the urine for experimental animals is increased. 
A most characteristic reaction occurs in the urine in the course 
of typhoid, as was first pointed out by Ehrlich, which depends 



108 TYPHOID FEVER 

probably on the abnormal decomposition of proteins in the body. 
This "diazo reaction," as it is called, is demonstrable by the ad- 
dition of a diazo benzene sulphonic acid reagent in two solutions 
to the urine. A positive reaction is evidenced by a reddish color 
in the foam produced in the course of the reaction. A simpler 
substitute for the diazo reaction is the urochromagen reaction, 
produced by the addition of a dilute solution of potassium per- 
manganate to diluted urine, which produces a bright yellow pig- 
ment in positive cases. 

Both these reactions are usually present in typhoid fever cases. 
The diazo reaction has been estimated by Brouardel and Thoinot 
to occur in ninety-seven per cent of cases. Its absence, then, is of 
distinct diagnostic value, as indicating that the case in question 
is not typhoid. A positive reaction, however, is no certain cri- 
terion of typhoid fever, inasmuch as it has been found to occur 
in other febrile diseases, particularly in measles, scarlet fever, 
pneumonia, and erysipelas. 

CHANGES IN THE LEUCOCYTE COUNT IN THE COURSE OF TYPHOID 
FEVER 

We have already discussed the characteristic localization of 
the typhoid bacillus in the bone marrow and the degenerative 
changes produced thereby. This localization in the bone marrow 
is associated with characteristic changes in the white blood cells 
of the circulating blood. Whereas the majority of infectious 
diseases, particularly those associated with localized purulent 
processes, are accompanied by an increase in the polymorphonu- 
clear leucocytes, typhoid fever, except in its very beginning, is 
usually associated with a diminution of these cells. The total 
leucocyte count during most of the course of the disease is di- 
minished, owing to an absolute and relative diminution in the 
polymorphonuclear neutrophiles. This leucopenia may be pre- 
ceded in the earliest days of the disease by a transitory hyper- 
leucocytosis. The count during the greater part of the disease 
characteristically ranges from two thousand to four or five thou- 
sand. Eosinophils are practically never found in active typhoid 
fever, and the large mononuclear cells are relatively increased. 
Intercurrent infections, such as pneumonia, may produce a slight 
rise in this leucocyte count, say to a count of ten thousand, which, 
however, would be distinctly below the count characteristic of 
an uncomplicated pneumonia. Convalescence and recovery are 
associated with a re-appearance of polymorphonuclear cells and 



THE DIAGNOSIS OF TYPHOID FEVER 109 

particularly of the eosinophiles. No direct relation between 
the degree of leucopenia and the prognosis is admitted by the 
majority of investigators. There does seem, however, to be a 
distinct relation between the relatively high leucocyte count or 
the artificial production of a high leucocyte count and a favorable 
prognosis. This point will be more particularly insisted on in 
connection with the chapter dealing with the treatment of the 
disease. 

SUMMARY OF THE DIAGNOSTIC VALUE OF THE VARIOUS LABORATORY 

TESTS 

In summary of this section, which deals particularly with the 
methods of laboratory diagnosis in typhoid fever, it may again 
be stated that no diagnosis of the disease should ever be made 
without laboratory aid. It is, moreover, doubtful whether a 
positive diagnosis of typhoid fever can be made in the absence 
of corroborative laboratory tests. Most important and reliable 
of these laboratory tests are the agglutination reaction and the 
demonstration of the typhoid bacillus in the circulating blood. 
Of less but still of distinct corroborative value are the diazo reac- 
tion, a total and differential leucocyte count, and the demonstra- 
tion of the organism in the feces, bile or urine. 

Blood cultures in the early stages of the disease and agglutina- 
tion tests from the second week onward are alone or together 
positive in the great majority of cases. In combination the two 
tests are almost absolutely conclusive. Their presence certainly 
proves typhoid fever; their absence strongly indicates its absence. 
Our own personal results in laboratory diagnosis may perhaps 
be summarized as indicative of the diagnostic value of these two 
tests when systematically carried out. We have recently sum- 
marized our laboratory examinations in 194 suspected cases of 
typhoid fever. Many of these cases could subsequently be def- 
initely shown to be not typhoid on the basis of purely clinical 
appearance. Thus, sixty-two of these cases in which the labora- 
tory findings were negative were subsequently found to be some 
other disease on clinical evidence. In eight cases a clinical pre- 
sumptive diagnosis of typhoid remained unchanged, and yet 
there was no laboratory evidence forthcoming to substantiate 
this diagnosis. A negative laboratory diagnosis means negative 
blood cultures and Widal, and subsequent to these examinations, 
negative findings in the stools and urine. If we are to admit, 
then, that these cases may have been typhoid fever in spite of 



110 TYPHOID FEVER 

negative laboratory evidence, it would appear that the possible 
failures in diagnosis of real typhoid cases by laboratory methods 
would be approximately four per cent. 

On the other hand, there were 124 cases in which the clinical 
and laboratory diagnosis agreed. Ninety-eight of these cases 
were treated by a type of vaccine therapy to be later described, 
and in them very careful and complete laboratory examinations 
were made. In these ninety-eight clinically typical cases of 
typhoid fever both the blood culture and the Widal were present 
in sixty-eight per cent. The blood culture was present in seventy- 
one per cent, and the agglutination test, taking a dilution of one 
to forty as a positive criterion, was present in 91.8 per cent. Either 
a Widal or a blood culture was positive in 97.3 per cent of the 
cases examined. A positive laboratory diagnosis in 2.7 per cent 
of the cases only depended on the demonstration of the micro- 
organism in the stools or urine alone. 



CHAPTER VII 

THE SEQUELS OF TYPHOID FEVER AND THE 
CARRIER CONDITION 

Typhoid fever is a serious disease not only through its intrinsic 
and complicating dangers, but owing to the numerous untoward 
results which follow in its train. The continued proliferation of a 
parasite in every part of the body over a period of days and weeks 
with persistent high fever and profound toxic metabolic changes 
in every organ and cell exerts a fundamental influence on the 
health of the body as a whole. A bacteriological recovery from 
typhoid fever by no means predicates immediate or even ultimate 
restoration to a previous normal. Recovery, again, from the 
disease itself may either be accompanied by disappearance of the 
typhoid bacillus, or by its persistence in one or several metastatic 
foci. Such persistence is frequently non-symptomatic, as we 
shall see. 

SEQUELS AFTER BACTERIOLOGICAL CURE 

We may for convenience discuss the sequels of the disease in 
accordance with the persistence or disappearance of the typhoid 
bacillus from the body. In cases of bacteriological cure the dis- 
appearance of the bacillus from the blood and later from the 
residual foci follows, pari passu, the abatement and disappear- 
ance of fever. The disappearance of bacilli in appreciable num- 
bers from the blood antedates a return to normal temperature 
by several days as a rule, but bacteria remain in certain parts of 
the body, gall bladder, intestine, and bone marrow in particular, 
for several days after permanent normal temperature, even in 
favorable cases. This persistence is evident clinically in the case 
of relapses, and in all probability by those slight exacerbations of 
fever which follow initial exertion or even excitement during the 
convalescent period. Complete convalescence is a matter of 
days or, in unfavorable cases, of weeks, after a normal tempera- 
ture has been reached. A re-establishment of weight and strength 
requires time even in the most robust, but later in convalescence 
weight may be taken on more rapidly and in excess of the pre- 
vious normal, when the metabolic functions of the cells have been 
slightly but not seriously injured. 

Ill 



112 TYPHOID FEVER 

In no inconsiderable percentage of cases recovery from active 
fever is followed by prolonged convalescence and debility. For 
example, Whittington in a recent series of cases found fourteen 
per cent in which recovery was abnormally slow. The debility 
which follows typhoid is usually not so evidently related to the 
illness that causes it, as in these cases we have mentioned; it is 
best shown by the greater susceptibility to other infections that 
is evident not only over a period of weeks but of years. Dublin, 
in statistics we have already quoted, has shown that death is 
more than twice as frequent in the three years following recovery 
from typhoid fever as under normal conditions. An increased 
susceptibility to tuberculosis is particularly evident. This fact 
was appreciated by the earlier clinicians and was especially em- 
phasized by Bartlett.* Woodruff has demonstrated the pre- 
disposition to tuberculosis in typhoid recoveries by showing that 
the death rates from the two diseases follow similar curves in 
thirteen countries. In Dublin's study of the increased death 
rate that follows recovery from typhoid, 38.9 per cent of the 
deaths in the three following years were due to tuberculosis. 
Sedgwick and MacNutt found that coincident with the reduc- 
tion of typhoid mortality through purification of water supplies 
the mortality from pulmonary tuberculosis decreases. 

Frequent temporary and at times permanent affections of the 
central nervous system follow typhoid. In addition to meningitis 
and brain abscess, which are more properly complications of the 
disease, authorities mention various forms of insanity charac- 
terized either by mania or melancholia, hysteria, and also more 
evident structural modifications such as neuritis, multiple sclerosis, 
anterior poliomyelitis and paralyses, either in the form of para- 
plegia or of hemiplegia. 

Derangements of the circulatory system are not infrequent 
sequels, and are in origin at least due to local deposition of bac- 
terial nests, probably complicated by a slowing of the blood stream. 
Arteritis, phlebitis, and particularly venous thrombosis (phleg- 
masia alba dolens) are well recognized. Murchison mentions 
thrombosis of the femoral vein in one per cent of his cases, and 
Whittington found thrombosis in three per cent of his cases. It 
is known to persist or recur for years, but fortunately it rarely 
produces embolism. Gangrene is regarded by Keen, who has 
collected 115 cases from the literature, as a sequel in typhoid of 
no inconsiderable surgical importance. 

* Loc. cit., p. 120. 



SEQUELS AND CARRIER CONDITION 113 



TYPHOID SEQUELAE DUE TO PERSISTENCE OF THE TYPHOID BACILLUS 
IN THE BODY 

The foregoing sequels that have been touched on are not inti- 
mately related to persistence of the typhoid bacillus in the body 
of the nominally recovered host. We are now to consider those 
far more important and numerically considerable cases of the 
disease which continue to harbor the microorganism for days, 
weeks, and at times for years after recovery from the fever. Such 
bacillus carriers are significant not so much from the standpoint 
of their own welfare as from the menace they offer in spreading 
the disease to others. Before proceeding to a detailed discussion 
of the real carriers and disseminators of typhoid infection, who 
generally themselves remain free from dangers of typhoid infec- 
tion, we may first consider those recovered cases in which per- 
sistent foci of typhoid bacilli are primarily of import to the car- 
riers themselves. 

Localized Pyogenic Foci 

The typhoid bacillus is not infrequently a pus producer, either 
alone or in combination with the staphylococcus or other micro- 
organisms. Ulceration of the larynx is not uncommon during 
the disease, and parotitis is another complication that occurs. 
Otitis media is present in 2.5 per cent of all cases, according to 
Keen, and it may persist long after recovery. Bennett reports 
two cases, in one of which the typhoid bacillus was isolated from 
the pus of the middle ear four years after recovery from typhoid 
fever. One of the most frequent localizations of the typhoid 
bacillus, both during and after the disease, is in or about the 
bones. The organism is present in the bone marrow throughout 
the disease and characteristically localizes there in experimental 
animals. After recovery the bones may be affected in three gen- 
eral forms: periostitis, necrosis, and caries. Of these, periostitis 
is most usual and the tibia is the bone most frequently affected, 
after which follow ribs, sternum and the vertebrae. The bone 
infections may be multiple and persist for long periods of time. 
Fogh isolated the bacillus twenty-three years after recovery. 
Tubby, Braxton and Hicks found the bacillus in an abscess of 
the forearm thirteen years after an attack of enteric fever. Kaspar 
describes re-infection in the form of two successive bone abscesses, 
the last of which occurred seven and one-half years after re- 
covery. 



114 TYPHOID FEVER 

Gall Bladder Infection 

In our discussion of the pathogenesis of typhoid fever we have 
already made reference to the uniformity and importance of 
localization of the typhoid bacillus in the gall bladder. As we 
have seen, the gall bladder serves as a reservoir and point for 
multiplication of the bacilli during the course of the active dis- 
ease; it supplies the intestinal tract with increasing numbers of 
bacteria as the fever progresses; offers a potential source for re- 
infections and relapses; and, finally, may serve as a continued 
menace to others. The gall bladder in typhoid is therefore worthy 
of a more detailed consideration at this point. 

Anton v. Fiitterer (1888), was apparently the first to show that 
the typhoid bacillus could be isolated from the gall bladder in 
fatal cases of the disease. He obtained the microorganism in two 
such instances, commented on the lack of bactericidal property 
in the bile, and suggested that the presence of the bacillus in this 
locality might serve as a potential cause of relapse. V. Fiitterer 
further showed that Bacillus pyocyaneus when injected into the 
circulation of rabbits could be found in the gall bladder in an 
hour and one-half. Similar experiments were later performed with 
the typhoid bacillus by Blackstein. In 1890, Gilbert and Girode 
found the typhoid bacillus in an acutely inflamed gall bladder 
removed during the course of the disease. It has since been 
shown repeatedly that the gall bladder contains the bacillus in 
the majority of cases of typhoid fever; Chiari 3 (1894) early ob- 
tained it in nineteen of twenty-two cases; Pratt somewhat later 
in twenty-one of thirty cases. It is obtained in nearly every case 
of the disease by modern methods. Scott actually found the 
organism in the gall bladder in twenty-four of twenty-eight posi- 
tive typhoid cases, and also in six of two hundred cases without 
history of the disease, a matter of considerable interest in rela- 
tion to the question of healthy carriers. Longcope 2 took bile 
cultures as a routine in suspected typhoid deaths when acting as 
pathologist to the Pennsylvania Hospital, and found the typhoid 
bacillus regularly in all positive cases. Human and bovine bile, 
at least, not only do not inhibit the growth of typhoid bacilli, but 
serve as a differential medium for its growth, as shown by Fraenkel 
and Kraus, a fact which has been made use of in Conradi's 3 dif- 
ferential medium for isolating the bacillus from the circulating 
blood, as we have seen. Stagnation of the bile apparently aids 
in the multiplication of the microorganism in the gall bladder 
(Pratt; Lowy), and it has been claimed by Posselt 2 that the 



SEQUELS AND CARRIER CONDITION 115 

formation of albuminous flocculi which follows the growth of 
the bacillus, still further perfects it as a culture medium. There 
is histological and bacteriological evidence which shows that 
typhoid bacilli multiply not only in the bile but in the walls of 
the gall bladder itself, which leads us to a consideration of the 
exact method by which it actually reaches the gall bladder and 
the lesions it produces there. 

The earlier observations by Gilbert and Girode, and Chiari 2 - 3 
in view of the then prevalent notion of typhoid as a purely intes- 
tinal disease, led them to assume that the bacillus reaches the gall 
bladder in an ascending route from the intestine. Birsch Hirsch- 
feld was probably the first to state that the microorganism reaches 
the gall bladder through the circulation, a conception which has 
since then been experimentally verified and generally accepted. 
Experimental infection of the gall bladder in rabbits with a careful 
study of the artificial carrier condition in these animals has at- 
tracted considerable attention since the work of Fiitterer, and 
particularly of Blachstein. Blachstein found that rabbits that 
have been given intravenous injections of cultures of the typhoid 
bacillus yield cultures from the gall bladder for days and weeks 
subsequently. The work of J. Koch, Chirolanza, Morgan, John- 
ston, Doerr, E. Blumenthal, Gay and Claypole, and others has 
shown not only that typhoid bacilli injected in this manner usually 
persist in the gall bladder for periods as long as nine months (Wein- 
furter) to be eliminated with the feces (Morgan), but, in short, 
produce a condition that is analogous to human chronic typhoid 
carriers. A certain percentage of rabbits die acutely after such an 
intravenous injection, but in the majority of instances perfectly 
normal animals survive the acute infection, the bacteria disap- 
pear from the blood in a few days, and finally become localized 
almost exclusively in the bone marrow and gall bladder, where 
they persist for weeks and months until the animal may eventually 
die of gradually increasing cachexia. This carrier condition may 
be produced with great regularity, in our experience, when cultures 
of the bacillus that have been grown on rabbit blood agar are 
employed for injection. Of forty-three normal rabbits that we 
utilized for this purpose, thirty-nine, or 90.6 per cent, became car- 
riers. This experimental carrier condition offers obvious ad- 
vantages for the study of the mechanism of gall bladder infection, 
of gall stone formation, and for testing various therapeutic agents 
designed to act on human carriers. 

The rabbit experiments have shown, first, that bacteria in- 
jected intravenously arrive very rapidly in the gall bladder: E. 



116 TYPHOID FEVER 

Blumenthal has shown, indeed, that they may be present there in 
ten minutes. Some difference of opinion has arisen as to the 
exact route traversed. Doerr, Lemierre and Abrami, and Nichols 
believe that the organisms pass from the portal circulation in the 
liver into the bile ducts. On the other hand, J. Koch and Chiro- 
lanza have shown not only that bacteria will reach the gall bladder 
promptly after ligation of the cystic duct, but have demonstrated 
nests of bacilli lying in relation to the capillaries of the gall bladder 
wall and apparently demonstrating ingress from this source. 
Personally we are inclined to believe that both routes are possible, 
as do Blumenthal and Baur, Jean, Hautefeuille and Sevestre. 
Passage through the liver seems a fairly certain and probably the 
usual route. Miss Lore Weber in our laboratory has been able 
to demonstrate typhoid bacilli histologically in transit from the 
blood spaces through the liver cell and into the bile capillaries. 
The matter is of more than academic interest in consideration of 
therapeutic measures. 

Although the typhoid bacillus reaches the gall bladder in human 
cases of typhoid regularly and promptly after invasion of the cir- 
culation, its presence there is not as a rule evidenced symptomat- 
ically. Jaundice, cholecystitis, acute or purulent, and later gall 
stones do, however, not infrequently occur. The first two of these 
possibilities may afford the first and, indeed, the only symptoms 
of typhoid infection. Jaundice as a symptom apparently varies 
markedly in different groups or epidemics of typhoid fever cases. 
Posselt, in a systematic enumeration of such cases in various re- 
ported groups, found icterus present in from 0.14 per cent to 
7.14 per cent of them. Sarrailhe and Clunet have recently de- 
scribed an epidemic of paratj^phoid in the Dardanelles campaign 
that was characterized by jaundice and epigastric symptoms of 
cholecystitis. The "pyriform epigastric tumor" of the gall 
bladder (Frerichs) is given by Brouardel and Thoinot as one of 
the possible diagnostic signs of beginning typhoid. Gilbert and 
Girode, it will be recalled, first isolated the bacillus from the gall 
bladder of instances of acute cholecystitis in typhoid. Perforation 
of the gall bladder and localized peritonitis is one of the rarer 
accidents that may happen. In the majority of cases no definitely 
localizing symptoms, except possibly pain on epigastric pressure, 
give evidence of the inevitable localization of the bacilli in the 
gall bladder. It seems probable, however, that minor histological 
changes occur in all cases. Holscher has noted the presence of a 
diphtheritic inflammation of the gall bladder in 0.25 per cent of 
two thousand typhoid autopsies. In artificially infected rabbits 



SEQUELS AND CARRIER CONDITION 117 

changes in the gall bladder are usually evident within a few days; 
the viscus gradually becomes distended even to two or three times 
its natural size. The bile, which at first may be thicker and 
darker than normal, assumes a milky appearance, owing to ac- 
cumulation of small white flocculi which on standing separate 
out, leaving a clear, nearly colorless fluid. A similar description 
of the gall bladder contents has been given in the case of acute 
cholecystitis in a proved typhoid carrier by Findlay and Buchanan. 
In rabbits, erosions of the mucosa appear and proceed until the 
muscularis coat is laid bare. In more advanced stages the gall 
bladder walls become thickened and the bile more nearly normal 
in appearance. Apparently identical conditions have also been 
found in chronic human carriers by Bindseil, by Messerschmidt 
and by Goebel. 

One of the most important sequels of the invasion of the gall 
bladder by typhoid bacilli is the production of gall stones. Naunyn 
noted as early as 1892 that a relatively large number of his gall 
stone cases gave a history of previous typhoid fever. Cushing 
found such a previous history in ten of thirty-one cases in the 
Johns Hopkins Hospital. Forster obtained a history of gall stone 
attacks in fourteen per cent of 173 chronic intestinal typhoid 
carriers. Klinger's 2 figures (1909) show 13.6 per cent of carriers 
with gall stone symptoms. These figures, as showing a causative 
relation, are surprisingly high when we consider that ninety per 
cent of individuals with gall stones never suffer from actual symp- 
toms. The instances of gall stones without history of previous 
typhoid are explicable, first, by the fact that other bacteria, as 
for example Bacillus coli and streptococci, undoubtedly produce 
them, and, secondly, we have in the case of healthy carriers un- 
doubted evidence of the invasion of the gall bladder by typhoid 
bacilli in the usual manner, without symptomatic typhoid fever. 
In Cushing's cases the typhoid bacillus was isolated from gall 
stones in an individual who gave no previous history of typhoid, 
and F. Blumenthal has reported two similar cases. 

Typhoid bacilli have frequently been obtained in pure culture 
from gall stones. Droba early found them as long as seventeen 
years after recovery from the disease itself. It is evident that 
these stones occurring in connection with typhoid bacilli may be 
rapidly formed ; in Pratt's third reported case they were present in 
stones removed on the eighteenth day of the fever. Milian ob- 
tained similar results on the sixteenth day. The actual mode of 
formation of these gall stones is of interest but by no means clearly 
understood. There is evidence that typhoid bacilli may pene- 



118 TYPHOID FEVER 

trate gall stones that are already formed. On the other hand, 
Kramer and Bachmeister have demonstrated that cultures not 
only of Bacillus typhosus, but of Bacillus coli and Bacillus pyo- 
cyaneus, when grown in sterile bile will cause crystals of choles- 
terin to separate out and to form small concretions. Richardson 
early showed that the typhoid bacilli which he found in the gall 
bladder were characteristically clumped, although more recent 
work by Venema and others would indicate that bile has in itself 
no real agglutinating action. 

Gilbert and Fournier proved the infectious origin of at least 
certain gall stones by injecting heated bouillon cultures of typhoid 
bacilli into the gall bladder of rabbits; they found small concre- 
tions in the bladder when such animals were subsequently sacri- 
ficed. Richardson 2 found gall stones in certain of his carrier 
rabbits. We have observed these formations in our rabbits, vary- 
ing in all degrees from pin-head, friable concretions to hard, 
facetted stones as large as a cubic centimeter in diameter, packed 
in and completely filling a distended gall bladder. 

It is evident that the condition in experimental rabbits presents 
a close analogy to the residual aspects of human typhoid infec- 
tion, except that persistence of the bacteria in the gall bladder of 
these animals is the rule rather than the exception. Normal rabbit 
bile, however, according to Nichols, is a less favorable medium 
for the growth of the typhoid bacillus than human bile. The 
typhoid bacilli soon disappear from the peripheral circulation in 
rabbits and coincidently agglutinins and fixation antibodies (Aoki) 
appear. The analogy is further strengthened by the fact that the 
appearance of the bacteria in the excreta in carrier rabbits is 
intermittent (Emmerich and Wagner) as in chronic human car- 
riers. When rabbits have first been immunized by subcutaneous or 
intravenous injections of typhoid vaccines, they do not become 
carriers on intravenous injection of a dose of living microorgan- 
isms, that produces the condition in normal animals (Gay and 
Claypole 3 ). They may, however, still be locally infected by in- 
jections directly into the gall bladder (Uhlenhuth and Messer- 
schmidt; Emmerich and Wagner), or even by intravenous doses 
when sufficient to overcome the increased bactericidal effect of the 
blood (Nichols). This latter condition again suggests chronic 
human carriers who are usually protected from generalized typhoid 
infection, although it is known that auto-reinfection may excep- 
tionally occur. 



SEQUELS AND CARRIER CONDITION 119 



THE CARRIER STATE 

Our consideration of the residual foci of typhoid bacilli in the 
human body has been not only to point out their intrinsic im- 
portance, but to serve as introductory to a description of the 
carrier condition. The persistence of typhoid bacilli in the body 
after recovery from typhoid fever indeed affects the individual 
less than it does the community. Incidental reference has been 
made in discussing the transmissibility of typhoid fever to the 
earlier observations of Gendron, of Budd 2 and of Klebs, 3 which 
indicated that fresh cases of the disease might be traced not 
only to typhoid patients, but to convalescents. The actual major 
sources of infection from convalescents in feces and urine were 
further indicated by Budd h 2 > 3 (1856) and by Petruschy (1898). 
We owe our true epidemiological conception of the importance 
of the typhoid carrier state primarily to Robert Koch, as stated 
in his address of November, 1902. Koch 2 there emphasized the 
importance of the typhoid patient and the typhoid convalescent 
as the primary source of further infection and recommended the 
establishment of experimental stations in certain parts of Ger- 
many in which typhoid fever was very prevalent. The first of 
these stations was established at Treves in 1903 under the direc- 
tion of Frosch, and by the year 1907 eleven such laboratories 
were running. To Drigalski is due the larger part of the credit 
of establishing on bacteriological grounds the concrete hypothesis 
suggested by Frosch that the typhoid bacillus may lead a sap- 
rophytic existence in the intestine long after recovery and be 
the cause of new cases, and further in collaboration with Con- 
radi the credit of proving the existence of healthy carriers. These 
and other investigations conducted in the German laboratories 
give us much of the information we now possess in reference to 
typhoid carriers, and this information, together with the intro- 
duction of typhoid vaccination, is responsible for the remark- 
able reduction of the disease in recent years. The data on this 
important subject are so recent and so extensive that they can- 
not as yet be grasped in their full significance. We attach par- 
ticular value to the efforts of Sacquepee, and of Ledingham and 
Arkwright to present comprehensive reviews of the typhoid carrier 
problem, and have made use freely of their authoritative mono- 
graphs in preparing this chapter. 



120 TYPHOID FEVER 

Classification of Typhoid Carriers 

Typhoid carriers may first of all be classified in respect to the 
mode of elimination of the bacteria. These modes of elimination 
are obviously dependent on the residual foci of typhoid bacilli, 
of which the most important is the gall bladder with elimination 
through the feces, and, secondly, the urinary tract with discharge 
through the urine. And, lastly, any of the localized purulent 
foci of typhoid bacilli, as otitis media or periostitis, may poten- 
tially, although rarely in practice, serve as sources of further 
infection. Our subsequent remarks deal largely with intestinal 
carriers, and for that reason we may at this point mention certain 
important facts concerning urinary carriers. 

Urinary Carriers. — Urinary carriers are much less common 
than intestinal carriers, although they may be individually more 
dangerous owing to the more indiscriminate distribution of urine 
and the relatively larger numbers that are discharged by this 
route. In certain instances the turbid urine may contain as many 
as a hundred million bacteria to the cubic centimeter. In the 
chapter on diagnosis we have already considered certain relations 
of the typhoid bacillus to the urinary tract. Konjajeff early 
(1899) found small metastatic nests of bacteria in stained sec- 
tions of the kidneys in certain typhoid cases, and Hueppe had 
isolated the organism from the urine in 1886. We know that 
by the second or third week of the active disease the bacillus 
can be found in from twenty-five to fifty per cent of cases in the 
urine, although it does not persist there as frequently as in the 
stools. Petruschy in 1898, pointed out the danger of spread 
of the disease from the urine of convalescent cases, and in the 
same year Rovsing reported a case of cystitis that had recovered 
from typhoid eighteen months previously, and found large num- 
bers of bacilli in a badly ulcerated bladder on operation. At au- 
topsy a month later numerous small abscesses were found in 
both kidneys. In some instances urinary carriers have been 
found who give no history of typhoid fever, a condition by no 
means uncommon, as we shall see in intestinal carriers. Bac- 
teria may be discharged for a limited period of time both in urine 
and feces, but the persistent carriers in the urine are usually re- 
stricted to this mode of dissemination. The principal source 
of the bacteria in urinary carriers is the pelvis of the kidney rather 
than the bladder, although a secondary focus may also be pres- 
ent in the latter organ. A chronic carrier condition is by no 
means dependent on profound structural changes in the kidney 



SEQUELS AND CARRIER CONDITION 121 

or the bladder, as in the case we have referred to. It is by no 
means certain that urinary carriers bear any relation to the cases 
of so-called nephro-typhoid or of cases of typhoid cystitis. As 
indicative of the proportion of urinary to intestinal carriers, 
Prigge 2 found that of 314 carriers only twenty-three, or seven 
per cent, were pure urinary carriers; and of these, sixteen were 
healthy carriers who had acquired the bacteria by association 
with typhoid cases. The duration of urinary carriers is probably 
not as long on the average as of intestinal carriers, owing to the 
fact that the condition is more accessible to local treatment. 
Prigge mentions a case of nine years' duration, and one of ten 
years has been reported by Meyer and Ahreiner. 

Typhoid carriers, again, may be classified in their relation to 
an actual attack of typhoid fever. Several such classifications 
have been made, notably by Conradi (1907), by Prigge (1909), 
and by Sacquepee (1910). The latter is by far the most com- 
prehensive and satisfactory. According to Sacquepee, carriers 
are comprised of the following groups and subgroups : 

Group I. Precocious or incubation carriers. These consist of 
those individuals who have ingested typhoid bacilli and are be- 
ginning to eliminate them without having as yet shown symptoms 
of typhoid fever. 

Group II. Carriers that have recovered from typhoid fever, 
who may be subdivided in respect to duration into: 

A. Convalescent carriers. Individuals who eliminate bac- 
teria up to three months after recovery. 

B. Chronic carriers. Individuals who eliminate from three 
months after recovery to indefinite periods of time. 

Group III. Healthy or paradoxical carriers — with no history 
of typhoid fever. 

We may proceed to an examination of the important facts 
characteristic of each of these groups of carriers. 

Carriers in Recovered Typhoid Cases. — Recovered cases of ty- 
phoid fever presented the logical material for the earlier investiga- 
tions of the carrier state. The elimination of typhoid bacilli for 
a period, which for convenience has been placed at three months, 
after recovery constitutes temporary or convalescent carriers. 
Such individuals were described first by Decobert, who found 
bacteria in the stools of twelve cases for from fifteen to twenty 
days after recovery from typhoid fever. 

Drigalski in 1904 reported on sixty-four cases both during and 
subsequent to recovery from the disease, and showed that bac- 
teria might also persist for months in the stools. 



122 TYPHOID FEVER 

We owe the complete demonstration of chronic or continued 
carriers largely to the thoroughness of German investigations. 
Continued examinations of the excreta of convalescent cases 
soon showed that excretion of typhoid bacilli may continue not 
only for a few weeks but for months and years. The direct evi- 
dence afforded by following authenticated cases for several years 
has since been supplemented by the demonstration of typhoid 
bacilli in the excreta of individuals who give straightforward 
though naturally less conclusive histories of typhoid fever, even 
as long as forty or fifty years previously (Bolduan and Noble, 
46 years; Gregg, 52 years). Such evidence shows that the carrier 
condition may persist for indefinite periods after recovery. It is 
apparent, then, not only that such a chronic carrier continues 
individually to be a menace, but that collectively their number 
is cumulative. It is, therefore, of importance to know in what 
percentage of recovered cases chronic carriers may be expected. 
As illustrative of efforts that have been made to determine this 
important point, we offer herewith a table summarizing results 
from the study of over 1,900 convalescent cases reported between 
the years 1905 and 1910 (Table XI). 



TABLE XI 






PERCENTAGES OF CHRONIC TYPHOII 


1 CARRIERS 


FOUND BY 


VARIOUS 


INVESTIGATORS IN A STUDY 


OP CONVALESCENT CASES 




No. of 


Percentage Carriers 


Author Date 


Cases 


forS 


mos. and more 


Lentz 1905 


400 




3 


Conradi 2 1907 


400 




0.5 


Klinger 1907 


482 




1.7 


Kayser 1907 


101 




3-5 


Semple & Greig 1908 


86 




11.6 • 


Park 2 1908 


68 




5.9 


Tsuzuki 1910 


51 




5.8 


Bruckner 2 1910 


316 




3.8 


Stokes & Clarke 1916 


810 




1.85 



It is evident from this table that continued excretion of the 
typhoid bacillus, largely through the feces, may be anticipated 
in four or five per cent of all recovered cases. There is no reason 
to assume that once the chronic carrier state has been established, 
at a period arbitrarily placed at three months after recovery, the 
excretion of bacteria becomes progressively less with succeeding 
months and years; in fact, all evidence points to the contrary. 
These percentages are certainly under the true percentages, owing 



SEQUELS AND CARRIER CONDITION 123 

not only to the difficulty in isolating typhoid bacilli from the feces 
of relatively normal individuals even when cathartics are em- 
ployed, but to the fact that the discharge of the microorganisms in 
carriers is characteristically intermittent. Thus, the high per- 
centage of 11.6 per cent reported from the Central Research 
Institute at Kasauli in India by Semple and Greig more nearly 
represents the true state of affairs, as the search for bacilli was 
made daily until the stools were repeatedly negative. But, if we 
assume as a minimum that five per cent of all recovered cases 
become chronic carriers and we know that over 150,000 recovered 
typhoid cases are still being produced each year in the United 
States, we have some 7,500 carriers added annually to a presum- 
ably cumulative list. It is evident how important any measures 
directed towards the detection and cure of these fundamental 
sources of further typhoid infection become. 

Precocious or Incubation-Period Carriers. — It has been clearly 
shown by a number of authors, notably by Mayer, by Simon and 
by Conradi, that certain individuals may excrete typhoid bacilli 
in their feces before they themselves actually come down with 
symptoms of typhoid fever. These individuals are particularly 
dangerous sources of infection because they are unsuspected. The 
exact mechanism by which this excretion takes place before the 
symptoms is not clearly understood. We have already seen that 
typhoid bacilli do not appear in considerable numbers in the feces 
until a generalized bacteremia has taken place and invasion of the 
gall bladder has occurred. In the majority of such instances, when 
such a distribution of the bacillus has taken place in the body, 
symptoms of the disease are already evident. On the other hand, 
we shall presently see that in the so-called healthy carriers a 
generalized invasion by the typhoid bacillus must have occurred 
with a subsequent permanent localization in the gall bladder, al- 
though no symptoms ever occur. It seems necessary to assume 
in the case of incubation carriers that the evolution of the disease 
symptoms has simply been delayed beyond the usual period fol- 
lowing general invasion of the typhoid bacillus. In the majority 
of instances these incubation carriers have been detected for rela- 
tively short periods before the appearance of symptoms, usually 
from two or three days to a week or so. Certain observations of 
Battlehner make it more than likely that incubation carriers, as 
we have suggested, simply represent a transition condition be- 
tween healthy carriers and the normal evolution of typhoid fever. 
Battlehner has reported seven incubation carrier cases, in four of 
which typhoid bacilli were detected in the excreta for from twenty- 



124 TYPHOID FEVER 

one to 117 days before the appearance of fever. The one case 
that was prolonged for 117 days is of particular interest in this 
connection; this individual, it would seem, may properly be re- 
garded as a healthy carrier who finally succumbed to autoinfec- 
tion. The agglutination reaction in the serum of this particular 
case was at first positive in a dilution of one to fifty, thus indicating 
a resistance to infection, but shortly before fever appeared it 
became negative. 

Healthy Carriers. — A thorough bacteriological survey of excreta 
in a general population irrespective of any previous relation to 
typhoid fever will show, as may be imagined from the fact that 
some of them have suffered from typhoid fever, a definite number 
of typhoid carriers. Four such determinations that have been 
made are included in the following table. 



OCCURRENCE OF 


TYPHOID 


CARRIERS IN THE 


GENERAL POPULATION 








Cases 


Percentage of 


Author 


Date 


Locality 


Examined 


Carriers 


Minelli 


1906 


Prison, Strass- 
burg 


250 


0.4 


Rosenau, Lumsden & 


1909 


Washington 


993 


0.3 


Kastle 










Prigge 


1909 


Saarbrucken 


10,841 


0.29 


Muller, P. T. 


1916 


Germany 


20,019 


0.8 








Including typhoid, 



paratyphoid and dysentery 

There is a singularly close agreement in these figures as to 
general occurrence of carriers, and an estimate of three carriers in 
every 1000 people must be regarded as extremely conservative 
when we consider the intermittence of the carrier state, the un- 
favorableness of normal stools for such examinations, and the 
difficulties in detecting the bacillus under the most favorable 
conditions. 

Our interest at this point attaches to the fact that if in investiga- 
tions of this sort careful inquiry as to the history of previous ty- 
phoid fever in positive carrier cases is made, it will be found that a 
certain number of individuals give no history of the disease. In a 
number of the earlier investigations on the distribution of typhoid 
bacilli, as for example those that were reported by Remlinger and 
Schneider in 1896, it was claimed that these organisms were found 
in the stools of perfectly healthy individuals. Owing to cultural 
difficulties, the typhoid bacillus was not clearly differentiated from 



SEQUELS AND CARRIER CONDITION 125 

the colon bacillus at this time, and it appears certain that it re- 
mained for Drigalski and Conradi to demonstrate that healthy- 
carriers of the typhoid bacillus really existed. Their observations 
in 1902 were corroborated two years later by Cler and Ferazzi, 
who found six positive transitory carriers among thirty-nine nor- 
mal individuals who had partaken of infected food that gave ty- 
phoid fever to others in the group. The actual percentage of these 
healthy carriers that may occur in a community was concretely 
expressed in the statistics compiled by Klinger 2 from a study of 
431 carriers detected in a population of 2,300,000 in South West 
Germany. Of these 431 carriers, 220 were chronic by the three 
months standard we have already given, and forty-four of the 
latter (20 per cent) gave no history of typhoid fever. Among the 
transitory carriers there were actually more healthy than re- 
covered carriers, 119 to 92 in fact. The total figures show that 
thirty-seven per cent of all the carriers found gave no previous 
history of the disease. 

These surprising figures probably exaggerate to some extent 
the proportion of healthy carriers that would be found in a general 
population. The material from which they have been drawn has 
been obtained from localities in which typhoid is rampant, and 
there are other figures which show that healthy carriers are par- 
ticularly prevalent in such districts. Klinger has shown that over 
0.6 per cent of 1700 healthy individuals in the vicinity of typhoid 
cases were carriers. Dennemark found four healthy individuals 
out of 250 (1.6 per cent), who had been exposed to cases of typhoid 
fever, who gave positive Widals and had typhoid bacilli in their 
stools. Scheller found eighteen healthy carriers among forty-four 
individuals who had used milk contaminated with typhoid bacilli; 
thirty-two others of the same group actually acquired the disease. 

As may be judged from the later statistics of Klinger, to which 
we have referred, the percentage of temporary carriers among 
healthy disseminators of typhoid bacilli is particularly high. 
Fornet, however, found that seventy-eight of 187 healthy carriers, 
whom he studied between 1904 and 1909, continued to excrete 
typhoid bacilli for months and years. The designation healthy 
carriers comprises, in addition to those who have actually suffered 
no symptoms of typhoid fever whatsoever, in other words, the 
true healthy carriers, many mild and unrecognized instances of the 
disease. These mild cases are particularly prevalent among chil- 
dren and are also characteristic in certain epidemics such as the one 
described in the French garrison by Billet, Le Bilian, Therault, 
Lamande, Lutrot and Louis, who describes all gradations of cases, 



126 TYPHOID FEVER 

some with constipation only, with fever lasting only two days, or 
even cases with complete apyrexia, and yet many of them giving 
positive cultures in the stools. Such cases in the absence of an 
epidemic would never be recognized as true typhoid, and yet 
would serve as potential sources for new infections. 

It should be repeated that the course of the typhoid bacillus 
through the body of the healthy carrier and its final localization in 
the gall bladder is precisely the same as in the recovered cases of 
typhoid fever. This fact has been conclusively proved by the 
finding of typhoid bacilli in the blood of healthy individuals (Con- 
radi, 2 Busse, Mayer, and Ebeling); and by the detection of the 
bacilli in gall bladder and gall stones of those with no previous 
history of the disease. For example, Scott could cultivate the 
typhoid bacillus from the gall bladder at autopsy in six out of 200 
individuals who gave absolutely no history of typhoid fever. 
Blassberg has not infrequently found typhoid bacilli in terminal 
cases of tuberculosis that gave no indications of typhoid fever. 

Importance of Carriers as a Source of Typhoid Fever 

In our consideration of the modes of transmission of typhoid 
fever we have found that they may in general be divided into con- 
tact and water infections. Contact infections are direct or in- 
direct, and the latter may form a chain of several and of different 
links. And, again, water containing Bacillus typhosus may reach 
the mouth directly or indirectly. In all instances the typhoid 
bacilli originate in excreta, particularly in the feces, either from an 
individual ill of typhoid or from a typhoid carrier. Any of the 
routes of typhoid infection outlined may be traced to a typhoid 
carrier as well as to a typhoid patient, but certain routes are more 
characteristically associated with each of these conditions. Ty- 
phoid fever is transmitted from patients more particularly by 
direct contact or by water, from carriers preeminently by indirect 
contact. Carriers transmit typhoid to others most frequently of 
all by the contamination of food. 

Carriers give rise either to individual cases or to epidemics, 
according to the intimacy of their relations with others and their 
occupation. They are particularly dangerous because they con- 
tinue a source of infection for indefinite periods of time and be- 
cause they are usually unsuspected. We have seen that there 
is an increasing agreement as to the relative percentage of typhoid 
cases attributable to each of the three great channels of infec- 
tion, contact, water, and milk. We have less information and 
therefore less agreement concerning the importance of typhoid 



SEQUELS AND CARRIER CONDITION 127 

patients and of typhoid carriers as the source of infection. This 
is due partly to the relatively recent demonstration of the carrier 
state on bacteriological grounds, and to some extent to the failure 
of epidemiologists to trace epidemics, to say nothing of indi- 
vidual cases, back to the previous individual from which the in- 
fecting dose was derived. That many cases of typhoid fever are 
due to carriers is undoubted, but exactly what percentage of them 
at any time or place is uncertain. In the following table we have 
grouped the estimates of a number of German investigators from 
material for the most part already presented in other connections. 

TABLE XIII 

ESTIMATED PERCENTAGE OF CASES OP TYPHOID FEVER IN GIVEN GROUPS 
ORIGINATING FROM TYPHOID CARRIERS 











Percentage Due 


Author 


Date 


Locality 


No. of Cases 


to Carriers 


Frosch 


1907 


Strassburg 


6708 


4.11 


Forster 


1908 


" 


386 


20.0 


Kayser 


1909 


" 


505 


9.5 


Schumacher 


1909 


Crov 


45 


26.6 


G. Mayer 


1910 


Bavarian Palatinate 


495 


32.3 



It will be seen that the tendency of these percentages of cases 
attributable to carriers rises with the later years. This is due in 
part to better criteria of estimation and greater success in tracing 
each case to its source. Thus, in Kayser's summary 26.7 per 
cent of cases were attributed to milk infection and at least part, 
probably the majority of these, were originally due to carriers. 
In the figures both of Mayer and of Schumacher the epidemiolog- 
ical work was very thorough. On most conservative grounds it 
would seem safe to attribute twenty-five to thirty per cent of all 
cases of typhoid to carriers. If all chains of cases are traced to 
the original link, it is probable that in even a higher percentage 
of cases carriers will be found at the beginning. Bruckner has 
reported on typhoid outbreaks that occurred in Saarbrucken in 
1911. There were twenty-eight such epidemic chains consisting 
each of from six to sixty-nine cases. Precisely one-half of these 
chains, fourteen in number, began with a carrier who in most in- 
stances communicated infection through food stuffs. Garbat 2 
has recently estimated that fifty-five per cent of all typhoid cases 
may be traced directly or indirectly to carriers. 



128 TYPHOID FEVER 

General Facts in Reference to Carriers 

There are certain facts of interest in connection with the carrier 
state in its relation to age and sex. There is an enormous pre- 
ponderance of females over males among the chronic carriers, 
something like five to one. The number of transitory carriers is 
practically the same in the two sexes. No direct explanation of 
the cause of this difference in the number of chronic carriers be- 
tween the two sexes is available, although several suggestions have 
been made that are at least probable. These differences, again, 
are in a similar proportion to the occurrence of gall stones, and 
both conditions may predominate in women, owing to feminine 
characteristics which tend to interfere with the portal circulation, 
namely, lacing, pregnancy and menstruation. 

Chronic carriers occur maximally at between forty and forty- 
five years of age and are rare in children, although the latter 
afford the highest percentage of transitory carriers. 

The actual danger of a given carrier is to a great extent de- 
pendent on the occupation which he or she follows. Food con- 
tamination accounts for the majority of cases that are derived 
from carriers, and those who have to do with the preparation or 
handling of food are the most prolific disseminators of the disease. 
Cooks, marketmen, who handle food stuffs, and milkmen have 
been the most frequent originators of carrier epidemics. The 
number and the distribution of cases will depend on the relation 
of the food preparer or handler to the general public. Cases due 
in this manner to food contamination are grouped characteristic- 
ally in houses or institutions served by a carrier cook, or along 
milk routes followed by a carrier milkman. Any grouping of 
people in close proximity also tends to enhance the infecting pos- 
sibilities of a carrier, apart from food contamination. Armies, 
prisons, and insane hospitals are particularly liable to epidemics 
originated in this manner. In a number of instances epidemics 
and scattered cases have been traced to carriers on shipboard 
(Sawyer 3 ). 

We have already referred to the intermittence in elimination 
of typhoid bacilli by chronic carriers. These differences would 
apparently lie beyond mere technical difficulties in detecting the 
typhoid bacillus, and seem at present inexplicable. This inter- 
mittence is evident not only f i om positive and negative bacteriolog- 
ical findings, but from variation in the number of bacteria excreted 
at different times. 

Efforts have been made to show differences in the virulence of 



SEQUELS AND CARRIER CONDITION 129 

bacteria obtained from different carriers, or, again, from carriers 
in contradistinction to typhoid cases. The only criteria of es- 
timation of such differences is the relative pathogenicity of dif- 
ferent strains of bacteria for experimental animals. This method, 
we believe, is of no value in relation to human infection, and, al- 
though there may be certain immunological differences between 
typhoid bacilli derived from blood or stool cultures, there would 
seem no method of proving experimentally that one strain is less 
liable to infect than another, or that another gives rise to a more 
severe form of the disease. 

Conversely, there are certain indications that suggest that 
newcomers when exposed to typhoid carriers are more susceptible 
to infection than those who have long dwelt in their vicinity. 
These indications, although interesting, are not supported by 
rigorous statistical or experimental proof and are subject to the 
same skeptical acceptance as are those instances of natural im- 
munity which we shall later consider. 

Typhoid carriers are for the most part personally unaffected 
by their condition, which is such a menace to others. They may, 
however, as we have seen, suffer from cholecystitis, from gall 
stones or from inflammation of the urinary bladder. In addition, 
there is the possibility of auto-reinfection, as has been shown by 
Levy and Kayser,' 2 and by Grimme. The two fundamental and 
as yet unanswered questions underlying the carrier state are, 
first, why the typhoid bacillus which promptly localizes in the 
gall bladder in all typhoid cases remains there in only four or five 
per cent of them; and, secondly, why, having persisted in the gall 
bladder, it fails to produce typhoid fever in the host at some sub- 
sequent period. The second question is obviously bound up in 
the explanation of acquired typhoid immunity. We shall later 
see that the protection against typhoid fever, which is relatively 
great and constant after recovery from the disease, is probably a 
tissue immunity; in the typhoid carrier it appears that a localized 
(lymphatic) tissue immunity may co-exist with a localized (gall 
bladder) tissue hypersusceptibility. 

The Detection of Carriers 

One of the greatest advances that could be made in the sup- 
pression of typhoid fever would be a rapid method for detecting 
carriers. In non-carrier typhoid recoveries, positive serum reac- 
tions are exceptional for any considerable period of time after 
recovery. Agglutinins, opsonins and fixation antibodies, on the 
other hand, are frequently but by no means invariably present 



130 TYPHOID FEVER 

in carriers. The agglutination reaction is positive in from two- 
thirds to three-quarters of those in whom typhoid bacilli persist, 
and more frequently in recovered than in healthy carriers. An- 
other possible diagnostic test for carriers might lie in the demon- 
stration of a leucopenia, which, as Leydhecker has shown, occurs 
not infrequently. 

The only certain and always necessary method in detecting 
carriers lies in an actual demonstration of the typhoid bacillus in 
their excreta. We have fully considered the methods for isolation 
of the typhoid bacillus from the stools and urine, many of which 
have been developed more particularly in connection with a study 
of the carrier state, and we need not consider them here in more 
detail. The laboriousness of these methods when applied to large 
groups of individuals, as is usually necessary in detecting a car- 
rier, is apparent. 



CHAPTER VIII 

GENERAL MEASURES OF PREVENTION OF TYPHOID 
FEVER 

We have finished our survey of the life history of typhoid infec- 
tion. We have considered the animate agent, the typhoid bacillus, 
which is the single essential cause of the disease, and have exam- 
ined in turn its methods of entering the human body, its develop- 
ment therein, and, finally, its methods and times of exit. From the 
latter point it is ready to begin again its characteristic and dan- 
gerous life cycle in another human being. It is obvious from all 
that we have seen that the typhoid bacillus is the only essential 
factor in the propagation of typhoid fever, although its task may 
be facilitated by a number of secondary factors extrinsic and in- 
trinsic to the life of its host. The prevention of typhoid fever lies 
therefore either in the destruction of the typhoid bacillus, or in 
preventing it from approaching human beings. 

From what we know of the modes of typhoid infection it is ap- 
parent that the typhoid bacillus may be dealt with at three points: 
on its egress from the typhoid patient or carrier; in transit from one 
individual to another; and, again, at the portals of entry of its 
prospective victim. Let us consider in this and the following 
chapters the methods of preventing the disease in accordance with 
these three loci of attack on the typhoid bacillus. 

THE PREVENTION OF TYPHOID FEVER AT ITS SOURCE 

Typhoid infection in common with other evils is best prevented 
at its source. It is perfectly true that typhoid bacilli from the 
moment they leave the ideal conditions for development furnished 
by the human body, tend rapidly to diminish in number, with few 
if any exceptions. This diminution in numbers is, however, from 
the viewpoint of prophylaxis more than offset by the greater dis- 
semination of the bacteria and thereby the more numerous and 
less evident contaminated sources which are produced. Although 
only a few of the original microorganisms may survive in any given 
locality, they may still be sufficient to produce infection. The 
prevention of typhoid at its source resolves itself into the proper 

131 



132 TYPHOID FEVER 

methods of dealing with excreta, and these methods will differ 
essentially in accordance with whether the particular source under 
consideration is a typhoid patient or a typhoid carrier, and so each 
of these individuals must be considered separately. 

Prevention of the Extension of Typhoid Fever from Typhoid Patients 

The extension of typhoid fever from known typhoid patients can 
and should be absolutely prevented. The full observance of even 
the simple rules laid down by Budd would suffice not only to pre- 
vent epidemics, as he did, but even single cases among those who 
surround the patient. The difficulty no longer lies so much in 
preventing new infections from known typhoid fever patients as 
from those in the incubation period of the disease, or those in whom 
diagnosis is not yet certain. There would seem no way of avoiding 
possible infection from apparently healthy incubation carriers, 
except in the observance of general rules of hygiene, such as wash- 
ing the hands before meals and after defecation and micturition, 
which, although frequently preached and rather generally appre- 
ciated, are rarely rigorously practiced. If every individual were 
to treat himself as a possible carrier in so far as personal cleanliness 
is concerned, this particular source of danger would be obviated, 
not only for typhoid fever, but for a number of other diseases as 
well. 

The earlier daj^s of typhoid fever are scarcely less dangerous 
from the point of further infection than the incubation period. 
Once the patient takes to his bed the danger must to some extent 
be diminished, even in the absence of diagnosis, for the area of 
contact with others is diminished and his hygiene passes under 
the supervision of others. The best method of general prophylaxis 
lies in the partial isolation of any febrile patient, rigorous steriliza- 
tion, or at least proper disposal of the excreta, and, as rapidly as 
possible, an assured diagnosis. The most certain method of ob- 
taining this diagnosis in earlier stages of the disease lies, as we 
have seen, in a blood culture, which should certainly be taken in all 
suspected febrile cases, and should be rendered more generally 
available for the general practitioner. The work of Conradi and of 
Klinger, 2 as tabulated by Ledingham and Arkwright, shows clearly 
that the danger from unsuspected and undiagnosed early cases is a 
real one. Their statistics show that the greater number of sec- 
ondary cases of typhoid are derived from primary cases in the 
incubation period and two earlier weeks of the disease, as illus- 
trated in the following figures (Table XIV). 



GENERAL MEASURES OF PREVENTION 133 



TABLI 


3 XIV 






IE OF INFECTION OF 


CONTACT cases fro 


(klinger 2 ) 






Incubation Period 




No 


. of Cases 


First week 






33 


Second week 






150 


Course of the Disease 








First week 






187 


Second week 






158 


Third week 






116 


Fourth week 






59 


Fifth week 






34 



The figures show the greater danger of early cases in which 
diagnosis is unsuspected or doubtful, and are the more striking 
when we consider that actually more bacteria are eliminated from 
the third week of the disease onward, both in feces and urine. 

The menace of typhoid fever patients is not only direct in that 
they may give rise to the disease in others, but indirect in that they 
may produce healthy carriers, who have been shown to be more 
numerous in the neighborhood of typhoid cases than elsewhere in 
the community, and who in turn may transmit infection. 

Once typhoid fever is recognized, prevention of the extension of 
the disease from that particular source may be and should be 
absolute. Such prevention depends on the following out of certain 
definite rules, applicable both to the patient and to those who 
attend him. First and foremost, typhoid fever is in most com- 
munities, and should be in all, a reportable disease, the reporting 
serving to signalize the presence of a definite but avoidable danger 
to those who come into the vicinity of the patient. The clinical 
history of the case should comprise as full an account as possible, 
not only of the actual duration of the disease before its recognition, 
but of any possible source of contagion to which infection may be 
traced. The history of excursions into the country, of drinking 
from suspicious water sources, of bathing in polluted streams in the 
neighborhood of recognized or unrecognized febrile cases, and the 
like, should be inquired after. The milk supply used by the patient 
in question should be ascertained in order that other cases that 
may occur on the same milk route may be correlated, and, when 
present, aid in tracing the individual, probably a carrier, who has 
contaminated the milk. 

As has already been stated, the patient should be isolated, 
preferably in a hospital, or if in a private house, at least in a room 



134 TYPHOID FEVER 

separate from other members of the family. The floors of the room 
should be cleaned by means of damp cloths wet with phenol solu- 
tion or bichloride of mercury, and every effort made to prevent 
raising a dust. No particular precautions are necessary in at- 
tempting disinfection of the air or in cleansing the walls. The 
windows of the room should be screened in order to prevent the 
access of flies to the patient's excreta. Every article or utensil 
that comes in contact with the patient should first of all be set 
apart for his particular use, and should be carefully disinfected 
before leaving the sick room. Bed linen and body clothes may be 
soaked in an antiseptic solution of bichloride or of phenol, and 
then preferably boiled. Eating utensils should be boiled before 
they are used again. If proper precautions are taken during the 
course of the disease, no terminal sterilization of the room is re- 
garded as necessary by modern public health authorities. 

The greatest possible care should be taken in the disposal of the 
excreta, particularly of the feces and the urine, from the typhoid 
fever patient. Sputum may either be expectorated directly into a 
glass or porcelain receptable containing five per cent carbolic acid 
or bichloride solution 1-1000, or collected on cloths and burned. 
The urine and feces are collected in a suitable bedpan, which 
should be separately sterilized after using by lysol, carbolic acid, or 
bichloride. The buttocks should be washed in a dilute solution, 
say one to 4000, of bichloride after defecation. Thermometers, 
particularly when used for taking rectal temperatures, should be 
kept in dilute phenol solution and rinsed in running water before 
being employed again. The feces after collection should be al- 
lowed to stand in a suitable disinfecting solution in proper amount 
and for a sufficient space of time. If the feces are not fluid, the 
masses should be broken by stirring, in order that the solution may 
penetrate thoroughly. A number of different disinfectants have 
been suggested for the purpose of disinfecting, among which may 
be mentioned bichloride of mercury in a dilution of one to 1000, 
added in proportion of from one-fortieth to one-tenth of the volume 
of material to be disinfected; formalin ten per cent in the propor- 
tion of one to ten; carbolic acid five per cent in the proportion of 
three or four to ten. For most purposes, on account of its relative 
cheapness and quicker action, the bichloride solution is usually 
preferable. Calcium hydroxide (milk of lime) may be added in 
proportion of one to eight. Both copper sulphate, as recommended 
by Vincent, or ferrous sulphate, as originally recommended by 
Budd, are also suitable disinfectants. Bleaching powder in a three 
per cent solution is also efficacious. The urine may be sterilized 



GENERAL MEASURES OF PREVENTION 135 

by the addition of bichloride, of formalin, or of carbolic acid, and 
the elimination of bacteria by this route is certainly to some extent 
inhibited by the administration of urotropin, the value of which 
will be more fully considered in connection with carriers. In 
general, contact with the disinfecting solutions should be for an 
hour or more. 

The bath water should be sterilized after using, the addition of 
one-half a pound of chloride of lime being sufficient to disinfect two 
hundred liters in thirty minutes. 

In addition, it may be pointed out that the dead bodies of 
typhoid fever patients offer certain dangers of infection. This is 
notably true in the performance of autopsies, where the greatest 
precaution should be taken by those engaged in their conduct. 
The external orifices of the nose, mouth and anus should be stuffed 
with cotton impregnated with a strong solution of bichloride or 
of phenol. 

A separate set of precautions should be taken by nurses or 
other attendants on typhoid cases. First of all, they should be 
fully protected by recent vaccination against typhoid fever, as 
will be fully specified in later chapters. Rigorous care should 
be taken to disinfect the hands by soap and water or by a mixture 
of denatured fifty per cent alcohol and liquid soap, as suggested 
by Joetten. When engaged in the intimate toilet of typhoid cases 
it is advantageous at times to wear rubber gloves, which are 
placed in a disinfecting solution when not in use, and rubber 
aprons may be utilized to advantage, particularly when bathing 
the patient. Great care should be taken by nurses to avoid, if 
possible, the preparation of food for others and even for them- 
selves, but when this becomes necessary, additional precautions 
in sterilizing the hands should be taken before handling any food 
stuffs. 

Prevention of Extension from Typhoid Carriers 

Any typhoid carrier is a potential source of typhoid fever, and 
the considerable proportion of all cases which are due to them 
has already been sufficiently emphasized. The dangers are great 
enough when carriers are recognized as such, but still greater 
during that often prolonged period during which they escape 
recognition. Short of comprehensive bacteriological examina- 
tions of whole communities, it will probably never be possible to 
recognize all of these unsuspected carriers. Certain precautions 
may be suggested, however, which will minimize the danger 
from this source. Carriers usually become recognized by careful 



136 TYPHOID FEVER 

epidemiological surveys in connection with repeated cases of 
typhoid fever in a given locality, in association with some par- 
ticular individual over a period of time, or in connection with 
some epidemic due to food, in the preparation of which he, or 
more frequently she, has taken part. In such surveys it is usually 
possible by a process of elimination to identify the carrier or 
carriers in a given group of individuals. The method by which 
this elimination is carried on will depend to a large extent on the 
individual skill, tact and experience of the epidemiologist. In 
dealing with people of various temperaments, who must be rigor- 
ously questioned as to present and past history, tact frequently 
is as important as knowledge. The past history of a prolonged 
fever, which may or may not have been designated as typhoid, 
is the first point of inquiry. Healthy carriers may frequently 
be detected by questions in relation to gall stone attacks or even 
to icterus. 

Final identification must rest in all instances on the demon- 
stration of typhoid bacilli in the excreta, and it may be neces- 
sary to examine many individuals and perhaps each several times 
to reach a final conclusion. 

Under ideal conditions of public health administration every 
recovered typhoid carrier at least would be known to the au- 
thorities and his relations to others properly controlled. Theo- 
retically no convalescent typhoid patient should be discharged 
without knowledge as to whether he is or is not a carrier of ty- 
phoid bacilli. In case he continues to excrete bacteria his lib- 
eration may at least be delayed, and before he returns to his 
usual life he should have been taught to appreciate his potential 
danger to the community. No convalescent may be discharged 
as normal until four negative bacteriological examinations of 
his stools and urine have been obtained. Flatten has suggested 
that the period of four weeks after the return to normal tem- 
perature, which is advisable for the welfare of the patient him- 
self, gives ample time for sufficient examinations of the stools, 
which in at least ninety per cent of cases become normal during 
this period. As a matter of fact, however, the excreta of con- 
valescents are seldom examined. This is true not only of cases 
in private practices but also, unfortunately, in most of even the 
best hospitals. Garbat 2 reports that according to answers to a 
questionnaire sent out by Dr. F. S. Graves only nine of twenty- 
four leading hospitals in this country examine the excreta of their 
typhoid patients before discharge. 

The early detection of carriers is very important in armies, 



GENERAL MEASURES OF PREVENTION 137 

not only in the body of troops itself, but in the inhabitants of 
captured towns, where typhoid has been prevalent. Systematic 
investigations of this sort have actually been carried out by Ger- 
man army physicians, according to Uhlenhuth. It is further 
highly desirable to detect carriers among cooks and others engaged 
in the preparation of food. In New York City a food handler's 
card is issued by the Board of Health, which is necessary in order 
to secure a position of this nature. In the absence of a bacteriolog- 
ical examination of this sort a history of previous typhoid fever 
might be taken into consideration in choosing among individual 
applicants for positions of this kind. The enormous amount of 
work necessary in bacteriological proof of carriers in general 
communities, when no line of typhoid cases points to some in- 
dividual, is indicated by the report of Muller, who found 165 
carriers in 20,019 soldiers examined in two months in the spring 
of 1916. 

As in the cases of typhoid fever, so in carriers, recognition of 
the condition at once renders preventive measures more efficacious 
and certain. It is by no means so easy, however, to prevent ex- 
tension of the disease from carriers, even when they are recog- 
nized, for obvious reasons. In the first place, the isolation of 
carriers even when they prove to be persistent sources of further 
infection is not legally possible in many communities. The in- 
jury they may do to others is manifest but intention in most 
cases is absent. At most, an individual may be accused only 
of carelessness, and many measures may be taken to avoid this 
particular danger. It has been suggested that isolation homes 
might be provided for recognized carriers, and under certain 
conditions it might be possible to induce or even legally to en- 
force residence in such a hospital, where every method that is 
available could be utilized in an attempt to restore them to their 
normal harmless condition. In institutions, particularly in 
asylums, isolation is strictly possible, and such isolation is not 
only desirable from the standpoint of prevention, but of great 
advantage, as affording opportunity for the further study of di- 
rect methods of attacking this important problem. 

It has further been suggested in connection with armies, where 
the typhoid carrier problem is of great importance, that recog- 
nized carriers could be pensioned, subject to certain restrictions 
bearing on their relation to others. 

The best that can be done at present in most instances, when 
carriers are recognized, is to outline a definite program for the 
carrier, to enlist his cooperation, and, if possible, to get him form- 



138 TYPHOID FEVER 

ally to agree to follow the rules that are laid down for him. The 
most important of these rules which the carrier should be urged 
to follow are, first of all, certain restrictions in reference to oc- 
cupation. No carrier should engage in the preparation or handling 
of food in any manner whatsoever. This includes particularly 
the handling of fruit and vegetables which are eaten raw, the 
handling of ice, of shell fish and of milk. Second, the carrier 
should report to the laboratory or public health bureau, from 
which he received his instructions, at definite intervals, and par- 
ticularly notify them of any new cases of typhoid fever which 
occur in his immediate surrounding. Third, he should be urged 
and instructed to observe strict personal cleanliness in the follow- 
ing ways: he should wash his hands carefully before eating and 
after defecation; he should use a personal towel; his body linen 
and bed linen should be sterilized, as in the case of typhoid fever 
cases, by immersion in an antiseptic solution and by boiling water. 
His stools should be examined at intervals for the possible de- 
tection of typhoid bacilli, but even when several examinations 
have been negative, the greatest reservation should be made 
in assuring the individual that he has returned to a normal con- 
dition and that he is really harmless to others. The excreta 
should be carefully sterilized, as in typhoid fever cases, when 
discharged into temporary receptacles or water closets that are 
not fly proof. 

We have very little knowledge as to what proportion of ty- 
phoid carriers who pass into the chronic stage of elimination, 
that is to say, beyond three months after recovery, spontaneously 
recover subsequently. It seems certain that recovery may take 
place at any subsequent period in the history of such an individual, 
but it is equally certain that certain individuals continue to ex- 
crete the microorganism throughout their life, as is evidenced by 
the detection of carriers for many years subsequent to recovery 
from the disease. So far, very little progress has been made in 
accelerating the recovery of carriers, although much information 
has in the past few years been gained in respect to the condi- 
tion, which will undoubtedly eventually lead to some specific 
method of accomplishing this end. At present, cure of the typhoid 
carrier would seem to be the greatest outstanding problem in 
connection with typhoid fever. As in our consideration of the 
carrier condition itself, we may begin discussion of modes of 
treatment that have been attempted by considering the urinary 
carriers first. 

The focus of multiplication of typhoid bacilli in the case of 



GENERAL MEASURES OF PREVENTION 139 

urinary carriers may lie, as we have seen, in almost any part of the 
tract. The original source of the organisms may be in the pelvis 
of the kidney or in the urinary bladder, or in both. It will not 
infrequently be found when ureteral catheterization is carried out 
that the urine from one kidney is sterile, whereas from the other 
it contains typhoid bacilli. In either case a recent method of 
treatment which offers certain advantages is the local irrigation 
with some disinfectants, particularly with silver nitrate in dilute 
solution. Urotropin (hexamethylamine) has been used for some 
time during the course of typhoid fever for preventive purposes and 
later as a means of treating carriers. In some instances carriers 
have ceased to excrete typhoid bacilli after repeated use of this 
substance. The majority of investigators, however, agree that 
urotropin is principally efficacious in limiting the number of the 
microorganisms during fever and convalescence, but its effect, 
even if thus limited, is considerable. Certain combinations of 
urotropin with other drugs would seem to have given better re- 
sults. Thus hetralin, which contains urotropin in conjunction with 
resorcin, and borovertin (urotropin plus boric acid) have given 
encouraging results, according to Ledingham and Arkwright. 

Irwin and Houston have reported success in a urinary carrier 
by the use of vaccines after rendering the urine alkaline with 
sodium lactate. Stokes and Clarke cured two chronic carriers by 
the use of urotropin and vaccine. 

Possible methods of cure for intestinal carriers have been sought 
ever since the detection of their existence. Such investigations, 
although for the most part discouraging, should be summarized 
in their general features. Surgical interference on the gall bladder 
has been undertaken in a number of cases on typhoid carriers. It 
would seem logical to assume that removal of this important 
metastatic focus might cure the condition for which it seems 
primarily responsible. Simple removal of gall stones with drainage 
as in the two cases reported by Dehler, although relieving stagna- 
tion of the bile, failed to cure the carrier state. Cholecystectomy 
was apparently successful in curing the carrier state in Grimme's 
cases, but failures have been the rule in others that have followed 
his procedure. This failure seems due to a continued propagation 
of the bacteria in the bile ducts which become dilated after re- 
moval of the gall bladder. 

Vaccination has been repeatedly tried as a means of curing 
carriers, but with very little result. Karell and F. Lucksch claim 
to have cured thirty-five out of forty-two cases treated in this 
manner, but in most instances the results by vaccination are 



140 TYPHOID FEVER 

frank failures, as could be imagined when we consider that the 
individuals so treated are already highly immunized against 
typhoid fever, as indicated by the presence of antibodies in 
their circulating blood, and little result could be expected in 
respect to the localized foci of the disease by still further increasing 
the systemic resistance to the bacteria. Another method of 
treatment of somewhat similar nature and of possible future value 
has been suggested by Herz, who produces the general reaction 
that may be caused by the injection of any foreign protein by the 
subcutaneous inoculation of ten cubic centimeters of sterile milk. 
Such a reaction is accompanied by an increase of leucocytes, and in 
Herz's cases apparently caused the bacteria to disappear from the 
gall bladder. 

The number, at least, of typhoid bacilli in the intestines of car- 
riers is undoubtedly influenced by the diet. G. Mayer in 1910 
suggested that the continued use of milk in typhoid convalescents 
reduced the number of bacteria and presumably had an effect on 
the occurrence of carriers. Liefmann in the previous year sug- 
gested sour milk for a similar purpose. In this connection it may 
well be questioned as to whether the rigorous carbohydrate diet, 
suggested particularly by Coleman, might not be of some service 
in this connection. This type of diet, which we shall discuss in 
more detail later, not only apparently spares the body proteins 
during the course of typhoid fever, but causes the typhoid bacilli 
to decrease relatively in the stools, as shown by Torrey. 

Many investigations in recent years have been concerned with 
the discovery of a possible type of chemotherapy which would 
affect typhoid bacilli localized in the gall bladder of carriers. 
Before proceeding to the experimental studies in this line that 
have been undertaken, we may refer to certain results of promise 
in connection with the treatment of human cases of typhoid and 
of typhoid carriers. Iodine in the form of potassium iodide has 
been utilized in conjunction with Fowler's solution by Tsuzuki 
and Ishida with promising results. When these substances are 
employed during the convalescent period, the bacilli are said to 
leave the excreta at an earlier period than when no treatment is 
employed. Kalberlah in a similar manner employed the tincture of 
iodine in conjunction with charcoal successfully in curing five 
chronic carriers. Rocek suggests the use of indol, which has an 
inhibiting action on the growth of the typhoid bacillus in vitro. 
He finds that normal stools contain indol, whereas typhoid stools 
do not. The most useful method of investigation for substances of 
possible therapeutic value in carriers is the typhoid carrier state 



GENERAL MEASURES OF PREVENTION 141 

in rabbits, to which repeated reference has been made. A con- 
siderable number of substances have been tried experimentally in 
this manner, although so far with very little encouragement. 
Among them may be mentioned chloroform, employed with 
negative results by Perusia and by Hailer and Rimpau, but with 
some success by Conradi, 5 who administered it in milk through the 
rectum. Other substances that have been employed are methyl 
iodide and iodoform in chloroform (Hailer and Rimpau), and 
tincture of iodine (Lowy). Nichols has recently suggested that 
rendering the bile alkaline by the administration of bicarbonate of 
soda may diminish the number of typhoid bacilli in the gall 
bladder, as evidenced by experiments in rabbits. Similar results, 
it will be recalled, were obtained in urinary carriers by Irwin and 
Houston. So far, however, no method of treatment of typhoid 
carriers can be recommended with any confident expectation of 
result. 

THE SUPPRESSION OF TYPHOID INFECTION IN ITS TRANSIT FROM ONE 
INDIVIDUAL TO ANOTHER 

Although the most logical and efficient means of preventing 
typhoid fever lie in attacks on the restricted sources of infection, 
it is clear that the great advances in the past have been made by 
measures directed against the vehicles of transmission of the 
disease. These measures of prevention center, first of all, in the 
proper disposal of sewage and the safeguarding of water supplies. 
Sewage should be discharged in such a way that it may be as far as 
possible removed from any water source or from any direct or 
indirect connection with food supplies. In the first place, sanitary 
toilets should be provided, which simply means that the sewage 
should enter as directly as possible into the main conduits. The 
preponderance of typhoid fever in rural communities is due to the 
unsanitary privy and absence of a closed system of sewage, but 
even the privy may be rendered less dangerous by careful disinfec- 
tion of the feces and by screening against flies. The importance of 
pure water supplies has already been evidenced in the charts in 
Chapter II, which show the morbidity of typhoid fever in relation 
to the relative purity of water employed in various communities, 
and, second, the reduction of mortality produced by changing from 
a more contaminated to a less contaminated supply. Water when 
utilized for drinking purposes, or, indeed, for any purposes of 
human need, should be repeatedly examined bacteriologically and 
chemically for evidence of fecal contamination. So far as possible 



142 TYPHOID FEVER 

it should be obtained directly from deep-lying springs which are 
not in connection with ground-water sources. The conduits which 
lead the water from the springs should be impervious to and pro- 
tected, particularly at the joints, from seepage from the sur- 
rounding soil. When water is obtained from open water ways, 
such as rivers and lakes, it should be carefully filtered through 
filter beds or disinfected by the addition of bleaching powder or 
other disinfectants. 

Another important means of prevention lies in the protection 
of food supplies from contamination either directly from sewage 
or from carriers. The use of human excreta for purposes of fer- 
tilization, particularly when the excreta have been obtained from 
hospitals, should never be permitted. Oyster beds should never 
be situated near the mouths of contaminated rivers, and vege- 
tables should be protected in transit from handling, and all food 
stuffs exposed in open markets should likewise be protected from 
human contact and, by proper screening, from flies. Another 
source of possible danger is the handling of ice by carriers, con- 
cerning which proper regulations are or should be enforced on 
railroad trains and steamships. Other possible sources of infec- 
tion that may be avoided in connection with trains and steam- 
ships are the common drinking cup and the common towel, which 
are fast passing out. Although recent authorities have attached 
relatively little importance to flies as agents in transmitting ty- 
phoid fever, it appears certain that under some conditions they 
may do so. The systematic destruction of flies would seem de- 
sirable for aesthetic reasons and for human comfort, apart from 
their danger as transmitters of infections. The removal of dung 
heaps, screening of houses, fly traps and fly papers are therefore 
judged worthy of all the attention that has been paid them, al- 
though the reasons that have stimulated this attention may at 
times have been over emphasized. 

MEASURES OF PROTECTING POSSIBLE VICTIMS OF TYPHOID INFECTION 

The last barriers of defense which stand before the individual 
in protecting him from typhoid infection are certain precautions 
that may be taken to avoid certain secondary causes that favor 
the occurrence of the disease. Although these predisposing fac- 
tors have already been mentioned in some detail, they may 
briefly be summarized at this point for the sake of completeness. 
Special care in avoiding sources of typhoid infection should be 
taken between the years of fifteen and twenty-five, during which 



GENERAL MEASURES OF PREVENTION 143 

period human beings are most susceptible to the disease. Cor- 
respondingly, groups of men composed of individuals between 
these ages, as in the case of armies, should be treated with ad- 
ditional precautions. Overwork and fatigue should, so far as 
possible, be avoided and the individual health should be pre- 
served and resistance increased by means of suitable exercises. 
The time of year in the case of army manoeuvres may be so 
chosen during the cool months as to avoid the greater dangers of 
infection during the summer. Proper sanitation of dwellings 
and pure air in houses should always be considered. In the case 
of armies, again, the point of intended encampment, particularly 
in localities in which typhoid fever has been epidemic, should 
be carefully considered from the standpoint of general health- 
fulness and the water supply afforded. Proper fly-proof latrines 
in such army encampments should be provided for reasons al- 
ready specified. Bathing in polluted streams and in swimming 
tanks which may be infected by excreta or by carriers should 
be avoided. Food should be cooked whenever possible, and 
water boiled when its source is suspected, and particularly when 
an epidemic of the disease is in progress. 

Last and most important of all in individual protection are the 
matters of personal cleanliness, concerning which many are in 
ignorance and still others, who are fully informed, careless. Popu- 
lar education is doing and will continue to do much to correct 
this frequent predisposing cause not only of typhoid but of other 
infections. Instruction as to washing the hands before meals 
is perhaps the most important single principle that should be 
inculcated from childhood. 

All the measures that we have suggested in this section are 
for the purpose of avoiding ingestion of typhoid bacilli. They 
represent the last barriers of defense external to the individual, 
but even when these precautions are neglected, protection against 
typhoid fever may to a large extent be ensured by proper specific 
immunization against the disease, as will be fully detailed in 
the following chapters. 



CHAPTER IX 

NATURAL AND ACQUIRED RESISTANCE TO TYPHOID 
FEVER 

Typhoid fever is a human disease and does not occur spon- 
taneously in any other animal species. Nor can typhoid fever 
be produced experimentally in the majority of the lower aniamls. 
A syndrome resembling human typhoid fever in its terminal as- 
pects may be produced, as we have seen, by the inoculation of 
rabbits intravenously, and possibly also by mouth, with pure 
cultures of typhoid bacilli, but the only condition resembling the 
human disease in practically all respects is the experimental 
typhoid fever of the anthropoid apes, as described by Metchnikoff 
and Besredka. Man, moreover, is not only the only animal sus- 
ceptible to infection with the typhoid bacillus, but is in general 
under natural conditions rarely protected from it. Some evi- 
dences of a relative immunity is evident, however, whenever a 
group of individuals are exposed to a given source of typhoid 
infection. A relative insusceptibility or protection is moreover 
evident when we consider the marked variations in the course 
of the disease as it occurs in different individuals. In any group 
of typhoid cases marked differences in the severity of the attack 
are evident, and even under conditions where the infecting dose 
must have been relatively the same, as for example when a num- 
ber of people drink from a contaminated water source or partake 
of the same dish prepared by a carrier. And not only may an 
attack of typhoid fever vary in a group of individuals from a 
mild or abortive attack of fever, lasting from a few days, to a 
severe and prolonged infection extending over a period of weeks, 
but certain exceptional individuals may show a reaction to infec- 
tion with the microorganism which is so mild as to pass unper- 
ceived, or be evidenced by a simple gastro-intestinal upset or by 
headache or malaise, lasting for a few hours. These mild, abor- 
tive or unsuspected forms of typhoid fever must, however, be 
regarded as real instances of the disease, inasmuch as such in- 
dividuals have been proved to harbor the typhoid bacillus not 
only in their intestinal canal but also in the circulating blood 
and gall bladder during and following such an attack. Such 

144 



NATURAL AND ACQUIRED RESISTANCE 145 

mild cases of typhoid fever represent instances of distinct nat- 
ural individual immunity or resistance when pains are taken 
to rule out those individuals who may have suffered from a pre- 
vious attack of the disease and who thereby have acquired the 
more general form of immunity following recovery, to which we 
shall refer presently. 

Certain very definite instances of natural immunity have 
been demonstrated in epidemics. Dennemark, for instance, has 
reported on 229 individuals who ate potato salad that had been 
prepared by a typhoid carrier. Twenty-two of these individuals 
came down within a few days with outspoken and regular at- 
tacks of typhoid fever. Fifty-nine of the remaining people had 
no fever but were found to give a positive Widal, and in four of 
these individuals typhoid bacilli were found in the stools. Scheller 
describes a milk epidemic in which seventy-two people over a 
considerable period of time drank milk contaminated by a car- 
rier. Forty-five per cent of them suffered from typhoid fever 
within a year, but fifty-five per cent, or forty individuals, re- 
mained uninfected. Of these forty individuals that seemed to 
have been naturally protected from the disease, eighteen were 
found to have typhoid bacilli in the stools or urine. The isola- 
tion of the organism from the latter source indicates that at some 
period the bacillus must have passed out of the intestine through 
the circulation into the urine, although no evidence of typhoid 
fever had occurred. Fornet, 4 in examining the stools of a number 
of individuals over a period of years, found 187 people with no 
history of typhoid fever who harbored typhoid bacilli, many 
of them for a period of months or years. Such individuals are, 
of course, those that have been denominated healthy carriers and 
are more fully discussed in our chapter dealing with that aspect 
of the disease. 

We have already remarked on the notable occurrence of ty- 
phoid fever among physicians and nurses. They have been 
shown to be perhaps eight times as liable to the disease as other 
individuals who do not come into intimate contact with cases of 
typhoid fever, and yet certain physicians and nurses remain 
unattacked by the disease in spite of repeated and at times care- 
less exposure. It seems quite possible that the general impres- 
sion that many physicians have gained that they have become 
immunized to the fever by absorbing small numbers of typhoid 
bacilli may have some foundation in fact. Brouardel and Thoinot 
have referred to this gradual immunization which may also exist 
in city dwellers as a process of mithridatisation. Such cases as 



146 TYPHOID FEVER 

these may be instances of acquired immunity that have been 
veiled by an unremarkable or mild attack of the fever. On the 
other hand, they may represent the natural immunity which is 
evident, as we have instanced, in every epidemic among certain 
exceptional individuals. 

We shall have occasion in a later section to refer in detail to 
the localized skin reactions of typhoid immunes to preparations 
of the typhoid bacillus. The typhoidin test described by Gay 
and Force has been suggested as an index of protection against 
the disease. This reaction, which occurs almost invariably in 
recovered cases of typhoid fever and for a limited and varying 
period of time in those that have been artificially immunized 
against the disease, is also found in some ten to fifteen per cent 
of supposedly normal individuals. In view of our experience 
with this reaction we may well question whether these people who 
give no history of a previous attack of typhoid fever and who 
certainly have never been vaccinated against it may not in fact 
have recovered from an undiagnosed or unsuspected attack of 
the disease. We have already reported (Gay and Claypole 3 ) 
the remarkable instance which occurred in a physician's family 
in which four individuals drank of a contaminated water source 
and of whom two developed frank cases of typhoid fever within 
a few days. The other two individuals suffered from malaise 
and headache for a day at about the time their relatives came 
down with the fever and had come to regard themselves as having 
passed through an abortive form of typhoid fever. On testing 
these four people with typhoidin they all reacted positively. In 
harmony with the alleged mithridatisation of physicians we may 
mention that we have records of several physicians who give 
positive typhoidin reactions with no history of the disease but 
following years of exposure to typhoid cases. 

It has been noted by a number of observers, for example by 
Louis, Vincent and Muratet, and McCrae, that newcomers in a 
given locality are more prone to suffer from typhoid than the 
inhabitants. Country people on coming to the city seem to be 
particularly prone to infection. This type of infection may be 
due to carelessness or ignorance as to the proper water supply, 
but, on the other hand, it may be due to a relatively increaesd 
susceptibility to unaccustomed strains of the typhoid bacillus, 
as has been suggested by Vincent and Muratet. 

Certain evidence has been given for the existence of a natural 
racial immunity against typhoid fever, which, however, it seems 
to us, is in all or nearly all cases better explained on other grounds. 



NATURAL AND ACQUIRED RESISTANCE 147 

Thus, Vincent and Muratet * would attribute, at least to some 
extent, the extraordinary freedom from typhoid of the Japanese 
troops in the Russo-Japanese War to a natural racial insuscep- 
tibility. They admit, however, that the occurrence of the disease 
in childhood may, together with systematic prophylactic im- 
munization, as we would agree, be the more likely explanation 
for this immunity. Vincent 4 has found that Arabs in Algeria 
are much less susceptible than the white foreigners to typhoid, 
presenting proportionately only one-eightieth or one-hundredth 
as many cases to the thousand inhabitants. Such individuals do 
not show agglutinins in their blood, but this by no means dis- 
proves that they are recovered cases. These observations have 
been confirmed by Widal. 2 

IMMUNITY FROM TYPHOID ACQUIRED BY RECOVERY FROM THE 
DISEASE 

It was specifically noted by Bretonneau in 1829 that individuals 
who had already suffered from typhoid fever very rarely again 
acquired the disease. Gendron in 1834, cites numerous detailed 
instances of this protection in individuals and families who, al- 
though exposed through nursing to acute cases of the disease, are 
protected from it in virtue of having already suffered from it at 
some previous time. According to Bartlett, Chomel noted that 
in one hundred and thirty consecutive cases in the Hotel Dieu, 
Paris, no individual gave a history of a previous attack of the 
disease, thus indicating that it did not tend to recur. Similar 
observations had been made by Nathan Smith in this country, 
and the combined evidence of these observers has been thoroughly 
confirmed by all subsequent investigators of this malady. 

But protection through recovery from typhoid fever is, as is 
true of most biological phenomena of this sort, relative and not 
absolute. Although it may be true that acquired typhoid im- 
munity is less absolute and enduring than the resistance acquired 
by recovery in other exanthemata (Curschmann), it does not 
apparently tend to "diminish progressively in subsequent years. 
Piedvache in 1849, gave evidence that the disease might recur 
in rare instances in the same individual, and a few years later 
Budd 2 f described four more exceptions to the usual condition of 
immunity which follows recovery from typhoid. It is interesting 
to note, moreover, that Budd's explanation of this protection is 
practically identical with Pasteur's exhaustion theory of im- 

* Loc. cit., p. 162. t Loc. cit., p. 33. 



148 TYPHOID FEVER 

munity and precedes it by some thirty years. Budd would ex- 
plain acquired typhoid immunity as due to the lack of proper 
nutritive substance for the self-propagating poison which, to fol- 
low his hypothesis, causes the disease, owing to their utilization 
in a previous attack. 

Since these earlier statements and recognition of the possibility 
of recurrence of typhoid fever in rare instances, numerous esti- 
mates have been made as to the exact frequency with which this 
recurrence actually occurs. It is perhaps generally admitted, as 
Liebermeister has stated, that recurrences in typhoid are more 
frequent than in small-pox, measles, scarlet fever and typhus. 
Estimates of the percentage of cases of recovered typhoid in which 
another attack may be anticipated have not, so far as we are 
aware, been given, and would perhaps be impossible to estimate 
exactly. The figures on which we estimate the liability to recur- 
rence of tj-phoid fever are based on a past history from individuals 
suffering from the disease rather than on the subsequent history 
of recovered cases. In other words, a knowledge of previous ty- 
phoid usually rests on information from the patient himself rather 
than on medical evidence. Estimates of this sort, although they 
vary considerably in the extreme instances, are on the whole 
fairly consistent. Drechsfeld estimates that 0.75 per cent of all 
typhoid cases offer a history of previous attack. Eichhorst in 
six hundred and sixty-six cases of typhoid fever found a history 
of previous attack in four and two-tenths per cent. The majority 
of observers would place the occurrence of a second attack between 
these two figures: Sinnhuber, for instance, three to four per cent; 
Curschmann, two and four-tenths per cent; Osier, two and two- 
tenths per cent (Ruhrah); Fornet, two per cent; Vincent and 
Muratet, one to two per cent; Seitz, two and fifty-four hundredths 
per cent. In epidemics where exposure is greater and the infect- 
ing dose larger or more virulent, the percentage of recurrences 
may be larger. Sawyer, and Kelly found that under conditions 
of massive infection eight and fifteen per cent of their cases, re- 
spectively, gave a history of previous attack. 

The majority of these estimates were made at a time when the 
differential diagnosis between typhoid fever and other similar 
maladies, particularly the paratyphoid fevers, could not have 
been made on the only correct basis of blood cultures or agglutina- 
tion tests. They are, therefore, open to the charge of marked in- 
correctness. ■ The separating out of the paratyphoid cases in the 
first or the second attack in any individual would on the one hand 
tend markedly to reduce the percentage of actual recurrences, 



NATURAL AND ACQUIRED RESISTANCE 149 

but, on the other hand, modern laboratory examinations in cases 
of mild fever, which might not be suspected of being typhoid, 
owing to a previous history of that disease, might reveal that the 
second infection was indeed a recurrence. 

This second possibility of a masked or mild second attack is 
rendered likely by the fact that in the recurrent cases that have 
been observed the second attack tends to be less severe than the 
first. Such a condition is not, however, invariable. At all events, 
it may be accepted, even on the basis of laboratory examination, 
that recurrences occur and that in some instances even three or 
four attacks may take place. Recurrent typhoid would, as might 
be expected, tend to occur at a somewhat later period in life than 
the ordinary time of occurrence of the first attack. The majority 
of cases in Eichhorst's series of cases, for example, came between 
the thirtieth and fortieth year. Recurrences, as already stated, 
usually occur in epidemics when presumably the infecting dose is 
larger and more virulent, a fact which again indicates that im- 
munity even of this fairly durable sort is relative and not ab- 
solute. It is probable, indeed, that any case of recovered typhoid 
could be re-infected if sufficiently large doses of the right strain 
of typhoid bacilli were ingested. 

THE NATURE OF PROTECTION AFFORDED BY RECOVERY FROM 
TYPHOID 

The nature of the protection against the disease in typhoid re- 
covered cases is of extreme interest and importance, although as 
yet by no means fully understood. All present evidence at our 
command would lead us to regard this protection as cellular rather 
than humoral in nature. The most important evidence in this 
regard is the fact that the Widal reaction tends to disappear soon 
after recovery from the disease, unless the individual remains a 
chronic carrier, in which case it may or may not be present. Alder- 
shof has found that sixty-nine per cent of typhoid recoveries lose 
their agglutinins by the seventh month. In eighteen per cent 
they may remain for years, but finally disappear. Fornet states 
that the Widal usually disappears in the first months but may be 
present in a low dilution for several years. 

One of the best evidences of the nature of the protection af- 
forded by a previous attack of typhoid fever is the carrier condition 
in some recovered cases, in which instances individuals continue 
to harbor and excrete the typhoid bacillus frequently for long 
periods of time, without themselves suffering from any manifesta- 



150 TYPHOID FEVER 

tions of disease. Such individuals may or may not give a positive 
Widal reaction. We have, further, frequently stated that there is 
reason to regard the so-called healthy carriers, who apparently have 
never had typhoid fever, as having in reality suffered a mild or 
unperceived attack of the disease, and as having actually had 
bacilli in the circulation, as well as a residual focus of the micro- 
organisms in the gall bladder or urinary bladder. These healthy 
carriers usually give a negative Widal test. The carrier condition, 
moreover, also presents evidence of the possibility of recurrence of 
the disease, inasmuch as a few instances have been given in which 
these people suffer from a generalized reinfection from the typhoid 
bacillus after years of a relatively normal carrier existence. These 
facts on the carrier state point to localized but not generalized 
cellular immunity. 

The evidence, then, is that the condition of protection acquired 
by recovery from typhoid fever is not due to the presence of cir- 
culating antibodies, as estimated from the agglutinin titer in such 
people. Estimations of other antibodies are not so accurate or so 
circumstantial that any definite statement as to their significance 
in typhoid recoveries can be made with certainty. There are, 
however, certain observations as to the presence of antibodies soon 
after recovery in typhoid fever, which, although not directly 
indicative of the nature of the long enduring immunity that usually 
follows this disease, are historically of interest as having led to 
artificial prophylactic immunization. Stern found that the serum 
of convalescent typhoid cases and of cases recovered several years 
previously may protect mice against infection from the typhoid 
bacillus, and Pfeiffer and Kolle 2 found that the serum of con- 
valescent cases gives rise to Pfeiffer's phenomenon of lysis when 
injected with the typhoid bacillus in the peritoneal cavity of guinea 
pigs. T hese latter experiments led to the work of these observers 
in protective immunization. There are not, so far as we are aware, 
any tests as to the protective nature of serum for long periods 
after recovery from the disease, and such a study would doubtless 
give information of extreme interest. In comparing the relative 
inefficiency of typhoid vaccination as compared with typhoid 
recovery, it is interesting to note that the humoral evidences of 
protection are more marked following the former procedure than 
in the latter condition, which is yet another argument in favor of 
the cellular nature of the stable immunity produced by recovery. 
It may be, as Jochmann has suggested, that resistance is due to 
some increased cellular power to produce antibodies rapidly follow- 
ing infection. 



NATURAL AND ACQUIRED RESISTANCE 151 



THE TYPHOIDIN TEST IN TYPHOID RECOVERIES 

Reference has been made under methods of diagnosis of typhoid 
fever to the use of tests for localized cutaneous hypersusceptibility 
to products of the typhoid bacillus. Skin tests of this sort are of 
recognized diagnostic value in prolonged diseases like tuberculosis, 
but, as we have seen, they occur so late in the course of typhoid 
fever as to be of little practical value. We shall see at a later point 
that one of the most important desiderata in connection with 
artificial immunization against typhoid fever is some method of 
determining the duration of protection afforded by this means in 
the individual case. In seeking a method of this sort, Gay and 
Force have described the "typhoidin test," which would seem at 
least of value as indicative of lack of resistance to typhoid infec- 
tion. As a point of departure in establishing the value of a test 
of this sort it was possible to show that those individuals who are 
best protected against typhoid fever, namely, typhoid recoveries, 
give a positive cutaneous reaction. In their early communications 
Gay and his collaborators (Gay and Force, Gay and Claypole 3 ) 
found that ninety-five per cent of people who gave an unquestioned 
history of previous typhoid fever (forty-four cases) show a positive 
typhoidin test. Later figures, both in our hands and in the expe- 
rience of other investigators, would tend to reduce this figure 
somewhat, and are in part dependent on changes and improve- 
ments in the technique of the reaction itself, which may well be 
described at this point. 

In the original typhoidin test Gay and Force employed a con- 
centrated glycerine bouillon extract of a single strain of typhoid 
bacillus prepared much as is old tuberculin. This preparation was 
applied by means of a sterile toothpick to a minute abrasion of the 
epidermis, and the reactions, in the form of a reddened areola 
extending for several millimeters outside the abrasion, were read 
in twenty-four hours, and called positive when they exceeded in 
diameter by two and one-half millimeters, a control spot of con- 
centrated glycerine bouillon prepared in the same manner but 
containing no typhoid growth. Estimations of positive reactions 
are in the majority of cases relatively easy, but, it must be con- 
fessed, are open to some subjective error. A number of investiga- 
tors have been able readily to confirm the contention of Gay and 
Force that the reaction performed in this manner does occur in the 
majority of individuals who have recovered from typhoid fever, 
irrespective of the antecedent date of the disease. On the contrary, 
it occurs in only relatively few instances in individuals who give 



152 TYPHOID FEVER 

no history of typhoid fever or typhoid vaccination. Thus, Mehler 
obtained the reaction in eighty per cent of typhoid recoveries, in 
one case in an individual who had had typhoid some fifty years 
previously. Gay and Force have mentioned recovered cases of 
forty and forty-one years' standing. Pulay found the reaction 
invariably in convalescents and old recoveries. These authors 
also agree that the reaction occurs only rarely in normal individ- 
uals who may be, as we have already suggested, justifiably sus- 
pected of having suffered an abortive or unperceived attack of 
typhoid fever. Austrian and Bloomfield alone obtained the same 
results in normals as in typhoid recoveries and typhoid vaccinated, 
owing to the fact that they used by far too large a dose of the 
typhoidin, a dose, indeed, containing as much typhoid extractives 
as would be contained in an ordinary immunizing dose of vaccine, 
and which in itself would be expected to give a local reaction in 
normal cases. 

Several modifications have been made which simplify and render 
this test far more uniform and accurate. Kilgore has suggested 
that a more objective reading can be made by the establishment of 
a typhoid quotient and careful measurements. The measurements, 
however, of the areola surrounding a cutaneous abrasion are most 
difficult to determine in some instances, and this improved method 
is no longer necessary in view of the subsequent improvements 
that have been made by Gay and Claypole, 3 and Force and Ste- 
vens. The latter authors, in particular, have standardized the 
reaction so that it may now be thoroughly recommended as differ- 
entiating typhoid recoveries and typhoid vaccinated from normal 
individuals. Its significance as indicative of protection against 
typhoid fever is a matter to which we shall refer at a later place. 
The modifications of Force and Stevens are, briefly, as follows: 

First, employment of an alcohol and ether dried typhoidin 
precipitated from plain instead of glycerine bouillon as originally 
employed, which is absolutely dried, kept in sealed tubes, and dis- 
solved in small amounts of carbolated saline for use over limited 
periods of time. 

Second, the use of a polyvalent typhoidin compounded from 
several strains of typhoid bacilli, chosen as representatives of the 
antigenic groups described by Hooker. 

Third, the intradermal administration of a carefully determined, 
minimal effective dose of the dried polyvalent typhoidin (0.000005 
grams in 0.05 cubic centimeters of 0.5 per cent carbolated saline).* 

* Through mathematical error the dose was published by Gay and Lamb as 
0.00002 grams. 



NATURAL AND ACQUIRED RESISTANCE 153 

And, finally, the reading of reactions at the end of forty-eight 
instead of twenty-four hours, which allows the non-specific irrita- 
tive reactions to subside. 

A positive reaction consists in the presence after forty-eight 
hours of a definite indurated papule surrounded by a reddish 
areola of at least five millimeters. 

With the test in its present form, Gay and Lamb obtained posi- 
tive results in seventy-five per cent of cases of recovered typhoid, 
who had suffered from the disease from two to twenty-two years 
previously. Normals with no history of typhoid or typhoid vacci- 
nation gave positive results in a little over fourteen per cent. 
Alstaedt, who has tested skin sensitiveness by a similar method of 
injecting a bacillary emulsion intradermally, finds that the reac- 
tions are usually positive with a clinical history of typhoid, at 
least for twenty years. 

It would appear from the results of Nichols 2 and of unpublished 
work of Gay and Claypole 3 with the earlier and now obsolete 
method that this reaction is not strictly specific in the sense that 
typhoid recoveries may also react to a solution of paratyphoidin A 
as well as to a solution of typhoidin. Thus, Nichols found in the 
case of individuals vaccinated against typhoid fever that sixty-six 
per cent reacted to paratyphoidin A and no more than seventy-five 
per cent reacted to typhoidin. He regards this result as militating 
against the use of this test as an indication of immunity against 
typhoid, because it may be generally accepted, as we shall later 
see, that typhoid vaccination does not protect against the para- 
typhoid fevers.* In the case of typhoid recoveries, with which we 
are for the moment primarily concerned, we have also found that 
some reacted when tested to paratyphoidin A as well as to ty- 
phoidin. Only half as many, however, reacted to the first solution 
as to the second, and in every instance but one the reaction was 
distinctly less with the paratyphoidin than with the typhoidin. 
The only individuals that showed a more marked reaction to para- 
typhoidin A were two who had suffered from well authenticated 
cases of paratyphoid A fever. It is probable that decisive informa- 
tion on this point will be obtained when a series both of paratyphoid 
and typhoid recoveries are tested with the two solutions. Similar 
doubts of the prognostic value of the typhoidin test as indicating 
protection against typhoid have also been raised by Meyer and 
Christensen, who in several extended articles have painstakingly 

* Similar reasoning would require that the serum of cases of typhoid fever 
should never give agglutination reactions with B paratyphsus alpha; we 
know, however, that such reactions occur not infrequently. 



154 TYPHOID FEVER 

repeated our animal experiments successfully, but have not been 
able to agree with our conclusions. Gay and Claypole 3 had en- 
deavored to explain the mechanism of the typhoidin reaction and 
incidentally to show the relation of a positive reaction to a con- 
dition of immunity by testing a number of vaccinated rabbits 
which were subsequently tested for their resistance against be- 
coming carriers, as already described. We found that fewer 
animals among those which became carriers on intravenous injec- 
tion gave positive typhoidin tests than among those which re- 
sisted such an injection, and thereby concluded that there was 
some relation between the two results. Meyer and Christensen 
amplify these results but draw the conclusion that since they are 
able to produce carriers at all in animals that give a positive 
typhoidin test, the test is no indication of protection. This failure 
to appreciate the essential relativity of biological phenomena is 
unfortunately rather common. It is not to be supposed that any 
form of immunization, even the most durable one afforded by 
recovery from typhoid fever, affords absolute protection. It has, 
indeed, been shown that there are a certain percentage of recur- 
rences of the disease, and, as we have already stated, we are con- 
vinced that under proper conditions any recovered typhoid case 
could be artificially infected with typhoid fever. The value of the 
typhoidin test is principally when negative, as indicating a failure 
to react sufficiently to typhoid extractives, rather than when 
positive, as a measure of the degree of protection against typhoid 
fever. This conception of its limitations in no way interferes with 
its value in connection with typhoid vaccination, as we shall see. 



CHAPTER X 

ARTIFICIAL IMMUNIZATION AGAINST TYPHOID 
FEVER 

Beumer and Peiper were the first to appreciate the possibility of 
an active immunization against infection with the typhoid bacillus. 
In 1887 they were able to prove that mice that have recovered from 
a non-fatal infection with living typhoid bacilli are frequently 
protected against subsequent, larger, and usually fatal doses of 
the same organism. In their most successful experiment they 
found that the best results were obtained by the gradual increase 
in dosage on successive inoculations, and they further suggest that 
it may be possible to immunize by means of sterilized cultures, 
which, as had already been shown, contain the toxic principle of 
the typhoid bacillus. They raise the question as to whether it 
might not be possible to immunize human beings by means of 
gradually increasing amounts of such killed cultures. In the fol- 
lowing year Chantemesse and Widal, following the work of Salmon 
and Smith on hog cholera, and of Roux and Chamberlain on 
malignant edema, found that they could protect mice against in- 
fection with living typhoid bacilli by means of sterilized cultures 
of the organism. 

The practical application of these experimental results in animals 
to the prevention of typhoid fever in human beings did not come 
until eight years later, following the discovery of the lysins by 
Pfeiffer. It was A. E. Wright, who, in a preliminary publication 
in 1896 followed by a fuller account by Wright and Semple in the 
beginning of 1897, first outlined a method of immunizing human 
beings against typhoid fever.* Wright grew cultures of the typhoid 
bacillus in bouillon for two or three weeks and then killed them by 
heating to 63° Centigrade for an hour, and preserved them with 
0.5 per cent phenol (carbolic acid). These vaccines were then 
tested for sterility and their toxicity carefully standardized by 
determining the minimal lethal dose for guinea pigs; the dose 

* Those who are interested in a polemic regarding the questioned priority of 
Wright's work over that of Pfeiffer and Kolle are referred to articles by 
Friedberger and by Wright, 2 published in the Centralblatt fur Bakteriologie, 
I. Abt., Vols. 44 and 46. 

155 



156 TYPHOID FEVER 

chosen for injection in human beings was measured by this toxicity 
for animals. Wright further utilized a method of counting the 
number of the bacteria in the preparation employed by comparing 
their number in a given dilution when mixed with a suspension of 
red blood-cells, the number of which could be accurately deter- 
mined. The dose of bacteria usually employed was from 750 to 
1,000 million. 

In the same year (1896) Pfeiffer and Kolle, following their work 
on the lysins in convalescent typhoid cases, immunized a few men 
and then estimated that protection had been produced from the 
increased content of their serum in agglutinins and bacterial lysins. 
They employed agar cultures of an avirulent strain of the typhoid 
bacillus suspended in salt solution and killed by heating to 56° 
Centigrade. An amount of this suspension, corresponding to one- 
tenth of an agar culture or something like two milligrams, was 
usually given on the initial injection, which was, as a rule, the 
only one. It is frankly admitted that the symptoms produced by 
this amount of culture were severe, and the method has since been 
modified in several ways to avoid these symptoms without essen- 
tially changing the principle involved. 

So much for the first two communications on typhoid immuniza- 
tion in human beings. They form the groundwork on which sub- 
sequent methods of vaccination against typhoid fever have been 
built. The various methods that have since been advocated are 
numerous. Metchnikoff and Besredka estimate that at least 
twenty different methods of vaccination have been described and 
advocated. Friedberger, 2 in his systematic review on typhoid 
immunization, enumerates twelve recognized methods. Paladino 
Blandini has actually attempted to test the comparative immun- 
izing value of seventeen preparations in guinea pigs. It is not 
our purpose to describe all these methods in detail, and the reader 
who wishes further information on them may consult the system- 
atic description of Friedberger or of Fornet 2 in regard to them. 
It will be well, however, to outline the most important of these 
methods as evidence of the scope that the investigation has taken 
in perfecting this type of immunization, and as indicating the 
tendency which would seem to be leading to its gradual perfection. 

PREPARATIONS OF THE TYPHOID BACILLUS THAT HAVE BEEN USED 
AS VACCINES 

Killed Cultures of the Typhoid Bacillus. — We have already men- 
tioned that the first two preparations, those of Wright and of 



ARTIFICIAL IMMUNIZATION 157 

Pfeiffer and Kolle, consist essentially in killed cultures, the one 
a bouillon culture, and the other a suspension of an agar culture. 
These two original methods have been followed by many modifica- 
tions. Thus, Loeffler took advantage of the fact that ferments, 
when dried, resist heating to a considerable degree without dete- 
rioration, and, regarding the antigenic property of the bacillus 
as ferment-like, he dried suspended agar cultures of the microor- 
ganism and then heated them to from 120° to 150° Centigrade. 
These dried cultures were then pulverized and used in weighed 
amounts for immunizing animals. He states that such a culture 
has lost little of its property to produce antibodies. Friedberger 
and Moreschi use a similar dried and heated culture in an amount 
corresponding to 1-4,000 oese in immunizing human beings. It 
should be noted at this point that the method currently employed 
of determining the immunizing value of these preparations lies 
in an estimation of the antibodies (agglutinins, lysins, etc.) pro- 
duced. As we shall later have cause to consider, these estimations 
offer an indication rather of the reaction of the animal body than 
a sure means of determining the degree of protection that has 
actually been afforded. 

As we shall see in a moment, the use of living instead of dead 
cultures has been warmly advocated by certain observers, and 
their assertions have apparently convinced several who are not 
quite willing to adopt such preparations owing to their possible 
danger, although they endeavor to approach them as far as pos- 
sible without actually using living microorganisms. It is ap- 
parently now the consensus of opinion that bacterial cultures are 
more antigenic when employed as nearly as possible in their living 
unaltered condition, and that heat in particular tends to alter or 
destroy essential, characteristic, antigenic properties. Several 
methods have been advocated for avoiding or obviating so far 
as possible the destructive influence of heat, and at the same time 
killing the bacteria. Leishmann advocates killing the typhoid 
bacillus at 53° Centigrade instead of at 56° or 60° Centigrade. 
Vincent, 2 ' 3 while fully recognizing the superior value of living 
cultures, regards their use as dangerous, and therefore kills the 
vaccines that he employs by means of ether. As will be later 
mentioned, we have used alcohol for the combined purposes of 
killing the typhoid bacilli and accelerating their flocculation and 
drying. Levy and Bruch killed their preparations by shaking the 
microorganisms in a medium containing galactose, and find that 
organisms prepared in this way immunize guinea pigs as well as 
the living cultures, and that these two preparations are far su- 



158 TYPHOID FEVER 

perior to heat-killed cultures in corresponding amounts. Fornet 2 
regards the unpleasant effects that are produced by the heated 
vaccine as due not only to the heating itself but also to the pres- 
ence of a large amount of albumin in the culture medium. He 
therefore grows his microorganisms in a medium containing only 
a small amount of peptone and kills them by heating to 55° Centi- 
grade for fifty-five minutes. Courmont and Rochaix killed their 
preparations by heating to 53° Centigrade. Nicolle, Conor and 
Conseil heat their bacteria to 55° Centigrade for forty-five minutes, 
and then to 52° Centigrade for thirty minutes more. Wasser- 
mann 2 insists that the antibodies produced by typhoid bacilli 
heated to 53° Centigrade are not markedly better than when they 
are heated to 56° Centigrade. Widal 3 believes that considerably 
higher temperatures may be used without harming the vaccine. 
Renaud *• 2 has advocated the use of ultraviolet rays to kill the 
bacteria. Kisskalt 2 kills and preserves his cultures by the addi- 
tion of phenol alone, a method which had previously been em- 
ployed for dysentery vaccine by Gay. Nicolle and Blaizot have 
killed their vaccines by the addition of sodium fluoride, and Ranque 
and Senez *■ 2 have described vaccines which have been killed and 
preserved by the addition of iodine. Achard and Foix mix their 
vaccine with oil before administering it. 

Bacterial Extracts. — In addition to killed cultures of bacteria, 
numerous extracts and preparations derived from them have 
been advocated for the purpose of immunization. Hahn has 
recommended the extract obtained from masses of bacteria by 
means of the Buchner press. McFadyen and Roland utilized 
liquid air as a means of killing bacteria and obtained from them 
an extractive substance. Neisser and Shiga have utilized free 
receptors obtained by autolysis of bacteria at body temperature 
in salt solution. Wassermann 2 has suggested a similar method 
with the autolysis produced by distilled water. He subsequently 
dries the extract obtained in this way and uses it as a vaccine 
powder (Impfpulver). At a later place we shall refer to the form 
of dried sensitized vaccine which our personal experiments have 
led us to recommend for immunization against typhoid fever. 
Dried vaccines have also been used as thoroughly antigenic and 
as giving better methods of estimation by Wilson and Dickson 
and by Brown. Brieger and Mayer have used a watery, filtered 
extract of shaken bacteria. Bergell and Meyer have used an 
extract of dried bacteria obtained by treating them with dilute 
hydrochloric acid. 

Various so-called soluble toxins of the typhoid bacillus have 



ARTIFICIAL IMMUNIZATION 159 

also been suggested for immunizing purposes by Chantemesse, 2 
by Werner, and by Rodet, LaGriffoul and Wahby. The extract 
of bacteria obtained by the method of Jez has also been suggested. 

Living Cultures of the Typhoid Bacillus. — Living cultures of 
the typhoid bacillus, usually more or less modified in their patho- 
genicity, have been warmly advocated by certain observers as 
producing the best immunizing preparations similar to those 
that have been employed in dealing with other diseases, notably 
in cholera (Strong). Castellani 4 uses an avirulent strain of the 
typhoid bacillus in the form of recent bouillon cultures which 
are then partially killed by heating to 50° Centigrade for one hour. 
Such a modified culture produces rather severe local and general 
symptoms, but when given twice would, to judge from Castel- 
lani's results, 5 produce a most satisfactory degree of immunity, 
which apparently has lasted in a number of cases on which he 
reports for at least four years. He suggests, as an alternative, 
that the first injection may consist of a killed culture followed 
by a living culture on the second inoculation. In addition to 
the superior immunizing properties of the living culture, it is also 
pointed out by Fornet 2 that the killed cultures in a given dose 
give more reaction because the split products of proteins, which 
are recognized to be toxic, are liberated by heat. Living cultures 
have also been employed by Pescarolo and Quadrone. The form 
of living cultures which has been advocated by Metchnikoff and 
Besredka will be considered under the next heading. As has al- 
ready been mentioned, living cultures are generally admitted 
to be of superior immunizing value by many who are not willing 
to adopt them, owing to the real or fancied dangers coincident 
with their use, and this has led to an attempt to approach the 
condition of living bacteria without actually employing them. 

Sensitized Cultures of the Typhoid Bacillus. — Active immuniza- 
tion by means of sensitized vaccines, that is to say, by cultures 
that have been first treated with an immune serum and then 
killed, was introduced by Besredka 2 in 1902. This method is 
not infrequently referred to as serovaccination, but it differs from 
the method properly called serovaccination suggested by Le- 
clainche in swine erysipelas and by Calmette and Salimbeni in 
plague, in that the excess of immune serum which these authors 
used is removed from the treated bacteria. It was found, as 
Besredka notes, that this excess serum tends to produce simply 
a passive immunity instead of the active immunity which is pro- 
duced by the cultures treated with immune serum, and washed. 
Apart from his original experimental work, Besredka did not 



160 TYPHOID FEVER 

deal with the practical aspects of sensitized vaccines until the 
experimental work on typhoid fever in apes was taken up by him 
in collaboration with Metchnikoff in 1911. In the meantime, 
however, sensitized vaccines had been tried out apparently with 
considerable success in at least three instances. Marie had been 
able to utilize the principle in treating rabies virus, Dopter in 
vaccination against dysentery, and Theobald Smith in a similar 
way found that he could produce active immunity by a balanced 
mixture of diphtheria toxin and antitoxin. This method of active 
immunization against diphtheria by a balanced (sensitized) mix- 
ture of toxin and antitoxin has recently been applied to human 
beings by von Behring. The principal advantages of this method, 
as originally claimed by Besredka, 2 are, first, it produces little 
or no violent reaction on inoculation in instances in which the 
untreated bacteria themselves are distinctly irritating, as for ex- 
ample with Bacillus pestis. Secondly, it gives rise to an im- 
mediate though transitory passsive immunity. Thirdly, it pro- 
duces, eventually, an active immunity which is as enduring and 
as rapidly formed as when untreated bacteria are used. The 
second contention as to the establishment of an immediate pas- 
sive immunity must, we think, be distinctly questioned in view 
of subsequent work. 

Not a little experimental work was done with sensitized typhoid 
vaccine before the work of Metchnikoff and Besredka, which 
will be taken up later. Paladino Blandini made a very careful 
study of seventeen different typhoid vaccines, comparing their 
relative immunizing properties. His experiments were carried 
out on guinea pigs, which were treated by the various prepara- 
tions and subsequently given an intraperitoneal dose of living 
typhoid bacilli. The vaccines tested include small doses of living 
cultures; killed cultures prepared after the method of Pfeiffer and 
Kolle, and of Wright; several "soluble toxin preparations" of 
the typhoid bacillus; nucleo-albumins; and extracts of the typhoid 
bacillus prepared in different manners. Compared with these 
preparations was the sensitized vaccine employed by Besredka, 
and Blandini was able to demonstrate that the latter was by all 
means the most protective. Not only were guinea pigs protected 
for at least four months, but it was found that their serum, which 
contains sensitizers, also protects normal animals against infec- 
tion. 

Ardin-Delteil, Negre, and Raynaud find that the use of sensi- 
tized typhoid vaccine in rabbits and human beings gives rise to 
relatively small amounts of agglutinins, but the bactericidal 



ARTIFICIAL IMMUNIZATION 161 

properties of the serum of those treated in this manner are much 
higher than of those treated by the ordinary cultures. This failure 
of sensitized or agglutinated cultures to produce potent anti- 
bodies has also been noted by Neisser and Lubowski, by Pfeiffer 
and Bessau, and by Broughton-Alcock. A number of authors 
have studied the antibodies produced by immunizing animals 
and human beings under identical conditions with sensitized or 
with non-sensitized vaccine. Among them may be mentioned 
Garbat and Meyer, Garbat, 3 Gay and Claypole, 3 Liebermann 
and Acel, 2 Grobl and Hever, Stoner, and Meyer and Kilgore. 
The majority of them agree that sensitized vaccines in general 
produce less potent agglutinins but better sensitizers or fixation 
antibodies than the untreated vaccines. Garbat and Meyer, 
further, have found that the serum of animals immunized with 
sensitized cultures protects passively better than the correspond- 
ing sera from animals that have been treated with plain cultures. 

In 1911 Metchnikoff and Besredka published their very impor- 
tant work on experimental typhoid fever in anthropoid apes. Hav- 
ing shown that a disease syndrome, which we have considered 
elsewhere in detail, could be produced in these animals in all 
respects similar to human typhoid fever, they then proceeded with 
a limited number of animals to make comparative tests of the im- 
munizing power of different vaccines. They found, in brief, that 
Vincent's polyvalent vaccine and a dead sensitized vaccine pre- 
pared by the Besredka method both failed to protect monkeys 
under the conditions of their experiments against subsequent 
infection with typhoid bacilli, but a few animals were protected 
perfectly by previous treatment with living sensitized cultures. 
From their protocols they draw the conclusion that the living 
sensitized vaccine is the only suitable means of preventing typhoid 
fever, a conclusion which, in view of the uniformly favorable re- 
sults that had been already obtained in protecting human beings 
by various killed vaccines, would seem unwarranted. Both Vin- 
cent, 4 and Gay and Claypole 3 have criticized the necessarily 
limited number of the animals in their experiments and the sweep- 
ing conclusions they have drawn from them. But, although not all 
their conclusions would seem justified, it would certainly seem 
demonstrated from the results that they and their followers have 
reported (Broughton-Alcock, Metchnikoff and Besredka, 2, 3 Bes- 
redka, 3 ), that the living sensitized vaccine gives little or no reac- 
tion, does not set up a carrier condition, and actually protects men 
very well against typhoid infection. 

Gay and Claypole 3 in an extended series of experiments have 



162 TYPHOID FEVER 

endeavored to test the comparative immunizing value of a number 
of different preparations of the typhoid bacillus. Their method 
consisted in determining the relative percentages of rabbits im- 
munized by different methods that could at subsequent intervals 
be infected with living typhoid bacilli in such a manner as to pro- 
duce permanent carriers. Under the conditions of their experi- 
mentation, employing cultures of the typhoid bacillus grown for 
many generations on rabbit blood agar, they were able to produce 
carriers almost invariably in normal control rabbits. As a result of 
these comparative experiments very distinct differences were found 
in the immunizing value of different typhoid preparations. In 
successive series of experiments it was shown, first, that untreated 
bacteria killed and precipitated by alcohol, dried, ground, and 
employed in weighed amounts, do not protect as well as typhoid 
bacilli that have been sensitized by a strong immune serum, 
washed and subsequently treated in the same manner. Second, it 
appears that in the case of unsensitized, dried bacteria the sedi- 
ment of bacterial bodies freed from the supernatant endotoxic 
fluid, as prepared from these dried cultures, contains the immuniz- 
ing principle almost in its entirety. The sediment of either sen- 
sitized or unsensitized cultures protects not only better than the 
supernatant fluid from these sediments, but actually better than 
the whole unseparated mixture; 'in other words, the supernatant 
extractive would seem actually to inhibit immunization. Finally, 
alcohol-killed, sensitized cultures protect almost as well as living 
sensitized cultures (Metchnikoff and Besredka), and the sediment 
of alcoholic, killed, sensitized cultures protects better than living 
sensitized cultures. 

Another matter of considerable importance in the choice of 
vaccines to be utilized in preventing typhoid fever would he in a 
decision as to whether a monovalent or a polyvalent vaccine is the 
more efficient. Most of the large armies, which represent the bulk 
of material available for statistics in typhoid vaccination, have 
used a vaccine containing a single strain of typhoid bacillus, as for 
example that employed in the English and the American armies. 
The idea of employing a mixture of several strains of the typhoid 
bacillus had been suggested by Wassermann in 1903 and later ap- 
proved and carried out by Vincent in the immunization of the 
French army. The idea of both these observers has been that 
since typhoid bacilli vary in their known reactions to immune 
serum and in their ability to produce immune sera on inoculation, 
they must vary in antigenic properties, and, conversely, that an 
individual immunized with a single strain would not be so well 



ARTIFICIAL IMMUNIZATION 163 

suited to combat an unknown infecting strain, unless a dominant 
strain had been used for immunization, which might be expected to 
produce antagonism to any variety of typhoid bacillus that might 
be encountered. Vincent 5 has further expressed the opinion that 
bacteria from the locality of exposure should be the ones chosen by 
preference in producing prophylactic vaccine, and Vincent and 
Muratet have given evidence for believing that a recurrence of the 
disease in a given individual may be due to the encountering of an 
organism differing antigenically from the one that gave rise to the 
first illness. It is with a similar viewpoint that Gay and Clay- 
pole, 3 Hatchell and Stoner, and others have also recommended a 
polyvalent vaccine. 

The choice of polyvalent vaccine was, however, it must be con- 
fessed, more or less empirical until very recently. It remained for 
Hooker, and independently for Weiss, to demonstrate that typhoid 
bacilli may actually be divided into definite groups on the basis 
not only of cultural but more particularly of their antigenic pecul- 
iarities. Their work would seem to indicate, first of all, that it is 
not safe to trust to immunity produced by a single strain of ty- 
phoid bacillus, and, second, that not only should several strains be 
used in compounding a vaccine, but that recently isolated strains 
are probably more antigenic than those that have grown for a long 
period of time on culture media. 

It may well be questioned why further modification of typhoid 
vaccine should seem necessary in view of the extremely good pro- 
tective results that have already been obtained in certain large 
groups of individuals, as in the American army, in which latter case 
a single strain of an old stock culture of vaccine has been employed. 
Since typhoid immunity, either artificial or acquired by recovery 
from the disease, can never become an absolute and invariable con- 
dition of resistance, why should further refinements in a process 
which seems so well perfected be attempted? These remarks, of 
course, apply not only to the question of polyvalency, but also to 
the various procedures, such as sensitization, various ways of kill- 
ing the bacilli, and the like, that have been employed in preparing 
the numerous types of typhoid vaccine. The only answer to such 
questions is and must ever remain that theoretical considerations 
based on the understanding of underlying principles will ever 
precede all practical advances. And, again, that advances lie 
not so much along paths that have already been trodden as in 
unexpected ways. No investigator in his theoretical studies can 
ever afford to let well enough alone. 



164 TYPHOID FEVER 



METHODS OF ADMINISTRATION OF TYPHOID VACCINE 

Typhoid vaccines are ordinarily and preferably administered 
subcutaneously. Injections into the muscles should be avoided, as 
they give rise to more unpleasant symptoms than when the bacilli 
are deposited in the subcutaneous connective tissue. Several 
attempts have been made to demonstrate that vaccine could be 
administered by the mouth and an equal degree of immunity 
thereby produced. Thus, Kutscher and Meinicke tried to im- 
munize guinea pigs in this manner, but were unable subsequently 
to demonstrate antibodies in their blood. "Wright found that the 
administration of from one to fifteen cubic centimeters of his 
vaccine by the mouth gave rise to no unpleasant symptoms in 
those who had previously been immunized by the subcutaneous 
method, but it produced diarrhea in an unvaccinated individual, 
and although the bactericidal property of the blood was increased 
for a short period of time after such immunization, this method of 
administration was abandoned. Vaccination per os has recently 
been suggested again by Tremolieres, Loew and Maillart, who 
advocate giving the vaccine in the form of pills. They state that 
this administration gives rise to no reaction, but they give no 
evidence of its value in producing protection. Nicolle, Conor and 
Conseil injected their vaccines intravenously and found that anti- 
bodies were produced rapidly even after a single injection. Fried- 
burger and Moreschi have used a similar method. These latter 
methods of ad minis tration intravenously or by the mouth are no 
longer, however, seriously recommended by anyone who has had 
much experience with preventive inoculation. 

The doses employed in immunization have varied in the hands 
of different experimenters and have, in general, tended to increase 
in number and amount of bacteria employed. Whereas the first 
advocates of typhoid immunization, Wright and Pfeiffer and 
Kolle, used only one or two injections, the number has subsequently 
been increased by most observers to three or four. The size of the 
dose is generally increased on successive inoculations, beginning 
with a dose of 125 to 500 million of bacteria, which are estimated 
by one of several methods; by counting the bacteria in a blood 
counter, or by comparison with red blood corpuscles, or, better 
still, by utilizing weighed amounts of dried bacteria. The most 
frequent doses that have been used when three inoculations are 
given have been 500, 1000, and 1000 million, but the total number 
of bacteria injected throughout the course of treatment would seem 
to be more important than the number of injections (Vincent and 



ARTIFICIAL IMMUNIZATION 165 

Muratet, Landouzy). Vincent estimates that at least 2000 million 
should be used in a course of treatment, and the number of in- 
jections may be diminished from the four which he originally 
advocated to two, provided the total number of bacteria injected 
remains the same. In the British army up to the time of the pres- 
ent world war it was customary to give only two doses of vaccine, 
which were increased to three in the American army with distinctly 
better results. We understand that the number of injections has 
since been increased to three in the English army as well. In 
France four and even five injections have been given, or, as men- 
tioned, the same amount in two or three injections. We personally 
have recommended three injections of 800 million bacteria or one- 
tenth of a milligram, but have recently been led to advocate in- 
creasing the number of injections to four or the size of each dose, 
owing not only to the occurrence of a few cases of typhoid among 
civilians that had been vaccinated, but also to the failure to ob- 
tain positive typhoidin tests after three vaccinations in a few 
cases, although it almost invariably has appeared when a fourth 
injection was subsequently given. 

The intervals of time which are allowed to elapse between in- 
jections are, again, a matter of importance. It has been customary 
to allow from seven to ten days to elapse between injections, based 
on no particular reason that we can find except that such a period 
would seem to represent the maximum of antibody formation 
following a single injection of antigen. As we have and shall re- 
peatedly mention, we believe that the antibodies in themselves are 
no sure measure of the degree of protection, but even if they be 
taken as an indication of the degree of reaction produced, as they 
probably are, it may be shown that the final results in antibody 
formation following a series of injections can be obtained fully as 
well by repeating them at shorter intervals. These facts have 
been clearly demonstrated in animals by the work of Fornet and 
Miiller, and Bonhoff and Tsuzuki, which has been further amplified 
by the work of Gay and Fitzgerald. In immunizing rabbits against 
the typhoid bacillus, it was further shown by Gay and Claypole 3 
that an equally durable grade of resistance could be produced 
irrespective of whether the vaccine was given daily or at three day 
or seven day intervals. We have, therefore, practiced prophylactic 
immunization in man by inoculations on alternate days rather 
than at longer intervals, a procedure of considerable value not 
only in assuring more rapid protection, but particularly in such 
emergencies as when troops are rapidly mobilized. 



166 TYPHOID FEVER 



THE IMMEDIATE EFFECTS FOLLOWING ANTITYPHOID INOCULATION 

The injection of typhoid bacilli or typhoid vaccine in human 
beings may produce a train of symptoms, which in mild degree sug- 
gest those of typhoid fever. These symptoms have, indeed, in 
certain hands, with certain types of vaccine, been so severe as to 
militate greatly against the widespread adoption of the method, 
although not in themselves of any serious import. As we shall 
presently show, vaccines vary considerably in the severity of the 
sj-mptoms which the}' produce, and it becomes a matter of no 
little importance, whenever it can be done without detriment to 
the prophylactic results which are aimed at, to employ a type 
of vaccine giving the least possible untoward effect, It is extremely 
difficult to correlate from symptoms described or not described, 
the experience of various authors, not only with different vaccines 
but with any given vaccine. The greater part of our information 
in reference to typhoid vaccination comes, as already stated, from 
the immunization of troops, young and healthy men, whose very 
choice of a profession indicates that they would be inclined to 
minimize personal discomfort. It is probable also that even those 
individuals who might be inclined to notice subjective symptoms 
are not encouraged to do so, as civilians might be in the hands of a 
family practitioner. There has been no agreement in the descrip- 
tion by various authors as to what constitute mild, moderate and 
severe symptoms, which further complicates any attempt to 
estimate the actual results that may be expected. 

The symptoms following antityphoid inoculation may be 
divided into local and general. The local reaction consists in a 
reddened induration or at times an edematous swelling with more 
or less pain, extending from the point of inoculation for from a few 
centimeters to the entire length of the arm. The general symptoms, 
any or all of which may occur after inoculation, comprise a rise 
in temperature, which may reach 101° or 102° F., malaise, dizziness, 
headache, vomiting, and general mental dullness and lassitude. 
Insomnia has also been encountered in some cases. Symptoms of 
this sort have been noted following immunization since the ob- 
servations of Pfeiffer and Kolle to the present time. Apart from 
individual variations in susceptibility to the injection not only of 
typhoid vaccine but of any foreign protein, may be noted certain 
general conditions which would seem to offer peculiar susceptibility 
to unpleasant reactions. It has been found, for example, that 
severe reactions are more likely to occur in tuberculous individuals 
and in those suffering from albuminuria and nephritis, e. g. Ton- 



ARTIFICIAL IMMUNIZATION 167 

nell, and Maurange. Maverick, Force and others have noted that 
recovered typhoid cases react more markedly than normal in- 
dividuals. Patients in the incubation period in typhoid may react 
violently to inoculations, although this very reaction may be 
followed by an aborting of the disease (Vincent and Muratet). 
Other conditions which predispose to more severe reactions are 
fatigue and overwork, or a heavy meal a short time preceding. 
Any acute disease, such as grippe or malaria, may accentuate the 
effect (Dziembrowski). Certain advanced organic diseases, arterio- 
sclerosis, diabetes, nephritis, myocarditis, or chronic pleurisy, 
are practically the only conditions which serve as distinct con- 
traindications to vaccination. In general, the second and third 
injections, possibly owing to the larger amount of vaccine usually 
employed in these injections, give rise to more symptoms than the 
first. Children usually react less markedly than adults with 
corresponding or even with the same dose. 

It is extremely difficult, for reasons that we have stated, to 
estimate the relative toxicity of any given vaccine in respect to 
others that have been employed, except in those rare cases where 
some individual has tried a number of vaccines in a comparative 
manner. It is pretty well admitted, both on the evidence of the 
authors themselves, of Friedburger, 2 and of others, that the 
Pfeiffer and Kolle agar vaccine cultures, killed by heating to 
58°-60°, produce rather severe local and frequent general symp- 
toms. Boehncke compared the Pfeiffer and Kolle vaccines with 
the vaccines of Wright, of Russell (U. S. army), and of Vincent. 
He found that the Pfeiffer and Kolle vaccine was the most toxic 
and that Vincent's was the least toxic of the other three. This 
latter conclusion agrees with observations by Louis and Combe, 
who obtained little reaction with Vincent's vaccine. The United 
States army vaccine, particularly when employed in civilians 
(Hartsock, Albert and Mendenhall), apparently gives rise not 
infrequently to distinctly unpleasant symptoms, although their 
occurrence is minimized by the majority of army officers who have 
reported their observations. The army vaccine is by no means 
peculiar in this respect, and, indeed, has been claimed by army 
officers to be less provocative of unpleasant results than other 
similar vaccines of this type simply prepared from heat-killed 
bacteria grown on agar. The untoward symptoms may to a large 
extent be avoided by injection late in the afternoon, by a light 
diet, and by avoiding injection following periods of fatigue. What- 
ever reactions do occur are usually more marked on the second 
injection which is normally twice as large as the first. 



168 TYPHOID FEVER 

Many efforts have been made, however, to avoid the toxic 
element inherent in vaccines of the ordinary type, either by re- 
moving some toxic substance present in the culture media (For- 
net 2 ), or the endotoxins of the bacteria (Johan), or, more par- 
ticularly, by the use of sensitized vaccines, the properties of which 
have already been described. Sensitized vaccines when recom- 
mended should never, however, be recommended simply on the 
ground of producing less reactions, because none of the reactions 
that have been discussed are sufficiently severe to contraindicate 
the use of any vaccine that gives rise to a durable type of im- 
munity. There are, however, a number of reports which would 
seem definitely to indicate that the original contentions of Bes- 
redka as to the peculiar inoffensiveness of sensitized vaccines are 
justified in practice. Broughton-Alcock and Garbat, 3 for ex- 
ample, have emphasized this point, and the Gay-Claypole vac- 
cine, which is not only sensitized but is also free from endotoxin, 
has shown peculiar freedom from unpleasant results. The free- 
dom from symptoms attending the prophylactic use of this vac- 
cine has already been reported by Force. 2 In a more recent sum- 
mary comprising 4,845 inoculations, Force has found that slight 
local reactions were produced in only twlve per cent and severe 
reactions in three and six-tenths per cent. The general symptoms 
were slight in 24.5 per cent and severe in only two and four- 
tenths per cent. The criteria on which the degrees of reaction 
are estimated are as follows: 

A. Slight local reaction: redness of the arm from 40 to 75 mm. 
in diameter. 

B. Severe local reaction: redness of the arm over 75 mm. in 
diameter. 

C. Slight general reaction: headache, lassitude, disturbed sleep, 
loss of appetite, a rise in temperature to 38° C. 

D. Severe general reaction: chill, diarrhea, a rise in tempera- 
ture above 38° C. 

Stoner and Kilgore 2 do not find any more severe reactions 
from the ordinary army vaccine than from sensitized vaccines, 
but in the particular series of cases with which they dealt the 
army vaccine produced few if any of the more severe symptoms 
which have been noted by other observers. At all events, it may 
certainly be stated that it has never been found that sensitized 
vaccines do produce the severer reactions, which have sometimes 
been caused by unsensitized vaccine. 

The reaction on the part of the blood cells to antityphoid in- 
oculations has been particularly studied in Germany during the 



ARTIFICIAL IMMUNIZATION 169 

present world war, and it has been found that in a general way 
the leucocyte picture resembles the one characteristic of typhoid 
fever. There is general agreement that each injection is followed 
by a leucopenia (Matthes, Glinchoff, Ziersch, Courmont and 
Rochaix 2 ), which is characterized by a relative increase in lym- 
phocytes (Labor; Lipp; Schneider; Hage and Korff-Petersen). 
Ickert reports that eosinophiles are for a time decreased follow- 
ing inoculation, but Lipp, Hage and Korff-Petersen, Ickert and 
Labor all find that the eosinophiles are ultimately increased and 
may remain so for several months following injection. A de- 
crease in the number of red blood corpuscles has also been noted 
by one or two observers (Tonnel). 

It may be recalled that the criterion on which Pfeiffer and 
Kolle based their expectation that a protection against typhoid 
fever would follow the inoculation of killed typhoid bacilli in 
human beings, was an increase of the lytic substances for the 
typhoid bacillus formed in the blood serum of individuals that 
had been treated in this manner. The subsequent years of fruit- 
ful study of antibodies, the agglutinins, the lysins, the tropins, 
the fixation antibodies, and the like have yielded an enormous 
number of facts of theoretical and of practical importance. We 
know that the presence of antibodies to any foreign protein sub- 
stance in an animal indicates that that particular animal has 
reacted in a specific manner to the protein or bacterium in ques- 
tion. We know that these antibodies are concerned directly or 
indirectly in certain ways in the actual protection of that par- 
ticular animal against such a protein, if it chances to be, as in 
the case of a bacterial protein, a cause of possible danger to the 
individual. We are far, however, from knowing the exact mech- 
anism of action of these antibodies, or which of them are more 
particularly concerned in the protection itself. In other words, 
the estimation of any given antibody indicates that the animal 
furnishing it has undergone infection or inoculation with the 
protein in question, but in reality, according to later conceptions 
is no true indicator of the degree of protection that is afforded 
against the harmful effects of the particular protein. This would 
also seem true in respect to resistance against the typhoid bacillus, 
which, as we have already stated in our consideration of immunity 
acquired by recovery from typhoid fever, must be regarded as 
cellular rather than humoral in nature. Antibodies have been 
shown to exist following artificial immunization against typhoid 
fever with various typhoid vaccines. The agglutinins, fixation 
antibodies and sensitizers have in particular been studied. We 



170 TYPHOID FEVER 

know that agglutinins are produced in the majority of instances 
in individuals who have undergone antityphoid inoculation. 
Wade and McDaniel, for example, estimate that some ninety 
per cent when tested a few weeks after completing treatment 
will give a positive Widal reaction. Dakeyne found eighty per 
cent of positive results within the first year. Klien has found 
that the Widal is highest about two months after inoculation, 
and these findings are in agreement with those of Bronner, Howell 
and Ziersch. Wade and McDaniel found that in the majority 
of cases the agglutinins disappeared in from six to twelve months. 
In their series they were positive in only sixteen per cent at the 
end of six months and in 11.7 per cent at the end of a year. Other 
observers, for example Dreyer and Inman, found the Widal posi- 
tive in all cases at the end of eight months after two injections 
of vaccine. Discrepancies of this sort in findings are dependent 
on several factors: first of all, the degree of dilution in which the 
serum would be expected to give a positive reaction to the ty- 
phoid bacillus; secondly, the amount of vaccine employed in im- 
munizing; and, thirdly, the type of vaccine itself, for, as we have 
already stated, sensitized vaccines are usually characterized by 
a failure to produce as strong agglutinins as unsensitized vaccine. 
The evidence, on which we have based the assertion that the 
presence or the intensity of the agglutinins in immunized in- 
dividuals is not a correct indication of the degree of resistance 
of the individual concerned, is briefly as follows. In the first 
place, the agglutinin test is usually negative within a short period 
of time in cases of recovered typhoid fever, than whom no in- 
dividuals show greater protection against this disease. The 
Widal usually becomes negative in a few days or months after 
recovery, and, at all events in very rare instances, remains posi- 
tive for the years during which this resistance to typhoid infec- 
tion is known to exist. The agglutinin test, moreover, is either 
negative or weak very frequently after complete immunization 
with sensitized vaccine, as compared with corresponding doses 
of unsensitized vaccine, and yet we know from the experiments 
of Gay and Claypole 3 that rabbits treated with the sensitized 
vaccine are more efficiently protected than the ones treated with 
unsensitized vaccine in corresponding doses, and become in- 
fected irrespective of the degree of the agglutinin titer of their 
serum. It has further been shown by Besredka, 3 Sawyer, 4 and 
others that sensitized vaccines may be expected to protect human 
beings against typhoid fever at least as fully as unsensitized 



ARTIFICIAL IMMUNIZATION 171 

It has been shown by a number of observers that the presence 
of antibodies against the typhoid bacillus is no certain indication 
of protection against infection with this microorganism. Thus, 
Marx found that a technician that had been immunized against 
typhoid and whose serum destroyed the typhoid bacillus in high 
dilution, was three months later infected with the very culture 
that had been used to immunize him. Crombie noted the oc- 
currence of a case of typhoid fever in a physician who gave a 
positive Widal reaction fourteen days before he came down with 
the disease. A number of such observations have been noted 
by Ruediger and Hulbert, and by Trowbridge, Finckel and Bar- 
nard. To summarize again our conviction in this matter, we 
would state that relatively high protection may exist in an in- 
dividual with or without agglutinins or antibodies in the circu- 
lating blood, and, conversely, the presence of antibodies in the 
circulating blood is no indication either of absolute protection, 
which probably never exists, or of the degree of protection against 
typhoid infection. 

We shall have occasion at a later point to discuss the typhoidin 
test, which has already been described in connection with ty- 
phoid recovery, as it occurs in individuals that have been arti- 
ficially immunized against typhoid fever. We believe this test 
to be of distinct value as indicating an actual resistance to typhoid 
infection, or at least, when negative, as showing a failure to react 
sufficiently to insure a normal degree of protection. 

A further reaction following immunization, which again sug- 
gests the clinical picture of typhoid fever itself, is the enlarge- 
ment of the spleen in some six per cent of the cases, that has been 
noted recently by Kammerer and Woltering, Frugoni, and Gold- 
sch eider. 



CHAPTER XI 

THE PROTECTIVE VALUE OF VACCINATION AGAINST 
TYPHOID FEVER 

It took some eight years (1896-1904) for Wright and others to 
interest the world seriously in typhoid vaccination as a means of 
actually preventing typhoid fever, and some five years longer 
before the methods laid down by German and English investiga- 
tors at the earlier date could be thoroughly tested out and ap- 
proved in practice. Any matter of statistical proof of this sort 
requiring the actual treatment and subsequent observation of 
large bodies of men would of necessity require time, and, in com- 
mon with all matters which affect so deeply the life and health of 
the individual and community, has met a wise and critical skep- 
ticism. Antityphoid inoculation has also, in common with all 
measures designed to protect the public health, been bitterly 
opposed by agitators who, when faced by a fancied infringement 
of personal rights, are blind to all calm inspection of evidence. 
The bulk of the statistics on which our final judgment must rest 
as to the remarkable efficacy of antityphoid vaccination, has been 
accumulated from the results of vaccination in armies. A large 
group of facts is now available and of thoroughly convincing na- 
ture, obtained not only from armies but also from institutions and 
among the civilian population, particularly when exposed to acute 
epidemics of the disease against which this method is designed to 
protect. The logical value of the proof that may be collected is 
extremely variable, as one might expect, depending not only on the 
accuracy of the observer, but also on the nature of the individual 
group experiments themselves. No statement derived from an 
indefinite clinical experience in administering the vaccine and 
observing failure or resistance from subsequent typhoid infection 
could, of course, be of any considerable value. We may classify, 
for the sake of comparing certain figures which we shall subse- 
quently adduce, the types of evidence on which our conclusions in 
reference to typhoid vaccination have been based, listing them in 
the order of their relative importance. 

We have, first of all, certain definitely controlled experiments in 
large numbers of soldiers in which comparison of the incidence of 

172 



THE PROTECTIVE VALUE OF VACCINATION 173 

disease has been noted in more or less equally divided groups of 
vaccinated and unvaccinated men in the same regiments, who are 
exposed to the same danger of infection. Such evidence is af- 
forded, for example, by the results obtained in the British troops 
in India, where vaccination has been voluntary. We have, more- 
over, in the partial vaccination of the inmates of institutions still 
more rigidly controlled experimental conditions. 

And, again, we have the accumulating evidence of a large body 
of men, as, for example, the United States Army, in which subse- 
quent to a certain period vaccination has been compulsory. In 
this case a diminution in the morbidity and mortality rate from 
this disease may be compared with the previous incidence of the 
disease in the same body of men. This evidence is not quite so 
convincing, inasmuch as the fluctuation and incidence of typhoid 
fever is known to be considerable and the introduction of other 
hygienic measures in the way of detection of carriers and purifica- 
tion of water supply may to some minor extent have aided in the 
remarkable diminution of the disease that has been brought about. 
In other words, a lessened danger to infection may have accounted, 
at least in part, for the reduction in morbidity that has taken 
place. 

Lastly, we have uncontrolled experiments, as among the civilian 
population, where conclusions are drawn by a number of different 
individuals, where the degree of exposure between vaccinated and 
unvaccinated must be extremely variable, and where the only 
conclusion of any significance would be a striking diminution in the 
total death rate of the vaccinated community. As we shall see, 
whereas a difference in morbidity and mortality rate from typhoid 
fever is of vital significance in comparing an army group of vac- 
cinated and unvaccinated individuals, it is of little value under the 
conditions of civilian life. As a matter of fact, it will frequently 
be found that the vaccinated individuals in a general community 
suffer a higher morbidity rate from typhoid fever than the general 
morbidity rate of the state or district from which they come, owing 
to the fact that it is usually those individuals who recognize that 
they are most exposed to infection who become vaccinated. 

We may proceed, then, to a consideration of the efficacy of 
typhoid vaccination by considering as impartially and as fully as 
possible what the actual result has been in the various groups of 
individuals that have been mentioned, beginning with the larger 
and controlled groups afforded by certain of the armies of the 
world. The armies and navies present not only controlled exper- 
iments but in most ways unusually standard hygienic conditions, 



174 TYPHOID FEVER 

and to some extent uniform conditions of exposure. They further 
represent standard vaccines given in a more or less uniform manner 
and properly prepared and conserved. 

THE ENGLISH ARMY 

When we consider that the sun never sets on the British Empire, 
it will readily be understood that no body of men has ever been 
exposed to more varied and often to greater danger of typhoid 
fever than the English Army. It is fortunate, therefore, that an 
Englishman, Sir Almoth Wright, was the first to deal effectively 
with the problem of the control of this disease by means of vaccina- 
tion. The varying conditions of exposure to typhoid to which the 
English Army has been subjected in various parts of the empire in 
peace times is evident from the following table compiled from 
statistics that have been furnished by Smith for the year 1898. 

TABLE XV 

MORBIDITY AND MORTALITY FIGURES FROM TYPHOID FEVER PER 100,000 OF 
ENGLISH TROOPS IN THE YEAR 1898 IN DIFFERENT LOCALITIES 

Locality Morbidity Mortality 

Great Britain 120 24 

Gibraltar 420 132 

South Africa 3290 577 

India 3600 1000 

Egypt 8100 2340 

High as is the mortality in certain colonies of the British Empire, 
it was even more remarkable in certain localities of India, where, 
for example, in the Khyber district the morbidity of this year was 
16,050 per 100,000 with a mortality of 4060. It is interesting, 
further, to compare the mortality rate in England for the general 
population during this same year, which was only seven. 

These figures, shocking as they are, represent the relatively low 
mortality from this disease in peace times which, as we have al- 
ready noted, is invariably increased during times of war. During 
the Boer War (1899-1902) in which 380,605 troops were engaged, 
the morbidity from enteric fever, which, to be sure, included para- 
typhoid as well as typhoid infections, in the English Army was 
57,684 cases, or a morbidity per 100,000 of 15,115 with a mor- 
tality of 2100. 

Between the years 1896 and 1904 Wright and his successors 
carried out over 100,000 inoculations in India and elsewhere. The 
distinctly favorable results of this labor are published in a series of 



THE PROTECTIVE VALUE OF VACCINATION 175 

articles, and certain groups of them are tabulated in the following 
table, which is aimed to represent the best controlled and sig- 
nificant figures from the results of typhoid vaccination in the 
English Army at successive periods before the present world war. 

TABLE XVI 

RESULTS OF ANTITYPHOID IMMUNIZATION IN THE ENGLISH ARMY. MORBIDITY 
AND MORTALITY PER 100,000 

Locality Vaccinated Unvaccinated Authority 

No. Morbid. Mortal. No. Morbid. Mortal. 
India 1900 10501 914 161 83135 1665 444 Wright 3 
India 1909 5473 380 36 6610 2830 390 Leishmann 

India 1910 58481 260 29 10794 1390 220 Firth 
Various col- 
onies 1913 10378 539 40 8936 3040 500 Report of the 

Antityphoid Com- 
mittee, London, 
1913 

The first results obtained by Wright, although encouraging and 
showing a di min ution both in morbidity and mortality, which was 
about two-fold in the vaccinated as against the unvaccinated, are 
still far behind the subsequent results that have been obtained. 
And, as Wright himself was first to point out, certain objections 
could be raised against the method, as was evidenced by certain 
untoward results that occurred in a few army groups shortly after 
immunization. In certain regiments in India severe and even fatal 
cases of typhoid occurred in considerable numbers in vaccinated 
individuals, and even when they did not occur so frequently in 
unvaccinated men of the same troop. The exact reason for this 
occurrence is probably not quite clear, but certainly would not 
seem to be due to the existence of a "negative phase," to which 
Wright attributed these unfortunate accidents. At all events, the 
Medical Advisory Board suspended antityphoid inoculations in the 
English Army for some eighteen months, beginning 1903 (Bruce). 
Wright's procedure was later ratified by the College of Physicians 
(Harrison), and has since proved generally efficacious, as the later 
results in the table indicate. The cause of failure in the earlier 
results was due in all probability to the fact that a single inocula- 
tion was given instead of the two or three which have subsequently 
been required, and also to some extent to the fact that the vaccine 
was more or less inactive through having been heated to 60° as in 
the original procedure recommended by Wright. It was pointed 
out by Ward that the incidence of typhoid fever among those who 



176 TYPHOID FEVER 

have received two injections of vaccine was distinctly less than 
among those who had received a single inoculation. 

The later results, some of which are summarized in Table XVI, 
show that there has been a distinct improvement since Wright's 
original method was supplanted by the modifications of Leish- 
mann, the most important of which consisted in requiring two 
doses of vaccine and killing the vaccine by heating to 53° and 
then adding phenol. Vaccination in the English Army has been 
and remains voluntary, although it was found by Firth that at 
the time of his report, 1910, in India, 82.3 per cent of the men 
had received the treatment, an increase in four years from 6.6 
per cent. His figures, moreover, demonstrate that the morbidity 
rate between 1906 and 1910 in India fell gradually from 15.6 to 
4.6 per cent, and the mortality from 3.19 to 0.63 per cent. The 
report of the English Antityphoid Commission published in 1913 
deals with the most representative and best controlled units of 
the English Army in respect to vaccination in different parts of 
the empire and investigates carefully the incidence of 19,314 
cases of the disease in respect to previous vaccination. Their 
conclusions, as evidenced in the table, may be stated in another 
way as showing that the morbidity in the vaccinated was only 
one-sixth of that in the unvaccinated, and the mortality one- 
ninth. Furthermore, only twenty-six of the fifty-six cases that 
occurred in the vaccinated were in individuals who had been fully 
vaccinated within two years. They recommend further inves- 
tigation of the types of vaccine and universal compulsory in- 
oculation. 

The protective value of antityphoid vaccination has been 
fully justified in the results obtained in the British Army during 
the present world war. Whereas ultimate statistical results are 
impossible at this time, certain figures that have been made public 
are of extreme and convincing value. Vaccination is apparently 
not yet a matter of compulsion in the English Army, although 
it is estimated by Fleming that ninety per cent of the men have 
actually been inoculated. Three injections apparently are now 
being given (Vincent and Muratet) instead of the two that were 
the routine before the present war. Mr. Foster made the state- 
ment in the British House of Commons that there had been 1501 
cases of typhoid fever in the British Army during the first two 
years of the war (to August 25, 1916). Of these, 993 cases oc- 
curred among vaccinated men and 508 among the uninoculated. 
If we are justified in estimating that ninety per cent of the total 
army had been vaccinated, it would mean that the vaccinated 



THE PROTECTIVE VALUE OF VACCINATION 177 

were approximately five times as well protected as the unvac- 
cinated. 

THE FRENCH ARMY 

Vaccination did not begin in the French Army until the year 
1911, when it was tried out in certain garrisons in France and 
in Morocco and Algeria. Several different types of vaccine have 
been tried, but the one recommended by Vincent, a polyvalent 
vaccine, with the organisms killed by ether, and later improved 
by the addition of strains of paratyphoid bacilli, is the one now 
in general use. The regular number of injections at first were 
four, but following a special report before the Hygiene Com- 
mittee in 1914, it was decided that owing to the exigencies of the 
war they could be reduced to two by increasing the size of the 
dose employed, for, as we have already stated, the actual amount 
of vaccine would seem to be more important than the number of 
injections. This shortened course, however, would not seem 
to have given as favorable results as in the smaller groups of cases 
in which four injections were given before vaccination became 
obligatory through the law passed the twenty-eighth of March, 
1914 (the Leon Labbe law). The excellent results obtained in 
the earlier sets of inoculations are summarized in the following 
table. 

TABLE XVII 

RESULTS (JF VACCINATION IN THE FRENCH ARMY BEFORE THE WORLD WAR. 
MORBIDITY AND MORTALITY PER 100,000 

Locality Vaccinated Non-Vaccinated Authority 

No. Morb. Mort. No. Morb. Mort. 

Avignon 1911 1366 687 225613202 Vincent and Muratet 

E.Morocco 1911 — — 6497 835 

Algeria 1912 — 9 — 1214 188 

Tours 1914 1646 488 19900 4340 

Particularly striking are the extraordinary results obtained in 
the epidemic which broke out in Avignon in 1911, which has 
been frequently quoted. It is probable, however, that it is more 
possible to avoid infection in epidemics like this in civilized sur- 
roundings than in a country like Morocco, where the sources 
of infection are not so evident. 

In spite of the law requiring vaccination, it would appear from 
the somewhat indefinite statistics that have become available 
since the beginning of the present war that not all the soldiers 
have actually been vaccinated. Whereas Rist estimated in 1916 



178 TYPHOID FEVER 

that 73.9 per cent of the army were vaccinated, certain German 
observers (Stursburg and Klose) found that only fifty-four per 
cent of 2782 French prisoners had been vaccinated and that 
typhoid was of relatively frequent occurrence among them, al- 
though its incidence was diminished markedly in those that 
had had four injections. It has been stated * that in the first 
year of the world war there were 1347 cases of typhoid of which 
891 were among the uninoculated and 256 were among the in- 
oculated. In the first group there were 155 deaths or 17.4 per 
cent mortality, whereas among the 256 inoculated there were 
only eight deaths, a mortality of 3.1 per cent. Vincent and Mura- 
tet state that re-vaccination is being practiced at yearly inter- 
vals, a single injection being given. Paratyphoid fever is, as 
we shall see, relatively frequent in the French armies, which 
we think must be attributed to a failure to have utilized the 
triple vaccine (typhoid, paratyphoid A and paratyphoid B) that 
Vincent recommended as a routine. There is evidence from some 
reports, for example Cade and Vaucher, that there must have 
been considerable irregularity in the number of injections given, 
and it appears evident that those that received the greater num- 
ber are the better protected. 

THE FRENCH NAVY 

Vaccination against typhoid was voluntary in the French 
Navy to March, 1915 (Chantemesse 3 ), and then became obliga- 
tory, four vaccinations being required. The numbers over a 
period from August 1, 1914 to April 1, 1916 of vaccinated and 
unvaccinated soldiers were approximately even, with about one- 
fifth as many cases among the vaccinated as among the unvac- 
cinated, and only one-seventh the number of deaths. 



THE RUSSIAN ARMY 

According to Tarassevitch, typhoid vaccination has been ob- 
ligatory in the Russian Army since August, 1915. The vaccines 
are prepared in various bacteriological institutes and sent to 
five control laboratories in the larger cities, where they are studied 
and tested for their absence from untoward effects. The vaccines 
are similar to those employed at the Pasteur Institute. No re- 
sults are as yet available as to their efficacy. 

* Editorial, J. State Med., Feb., 1016, Vol. 24. 



THE PROTECTIVE VALUE OF VACCINATION 179 



THE ITALIAN ARMY 

Triple vaccines were employed in 1912 and 1913 in Cyrene, 
Tripolis, and finally in Italy (Vincent and Muratet). In the 
earlier part of the work Pfeiffer-Kolle vaccines were used inter- 
changeably with Vincent's vaccine, but in Northern Africa it 
became evident that Vincent's vaccine affords far better protec- 
tion, as is evidenced from the following table which we borrow 
from Vincent and Muratet (Table XVIII). In small groups of 
individuals, since Vincent's vaccines have been employed, very 
good results have been obtained. 

TABLE XVIII 

MORBIDITY FROM TYPHOID PER 100,000 VACCINATED IN THE ITALIAN ARMY IN 
AFRICA 

Vaccine Employed No. of Injections 

12 8 

Vincent's triple vaccine 440 270 30 

Pfeiffer-Kolle vaccine 1070 690 720 



THE JAPANESE ARMY AND NAVY 

The incidence of typhoid fever in the Japanese Army before 
and after the introduction of vaccination has been summarized 
by Yagisawa. Whereas during the Russian and Chinese wars 
(1897-1903) the incidence averaged five hundred per 100,000 
with a mortality of one hundred, and later rose to eight hundred 
with a mortality of one hundred and thirty, in 1908 with the 
introduction of vaccination (A. Netter) the morbidity dropped 
to seventy and the mortality to eight. There were approximately 
one-tenth as many cases in the vaccinated as in the non-vaccinated 
(Chantemesse 4 ). 

In the Japanese Navy typhoid fever increased from 1902 to 
1907 until it had reached 920 cases per 100,000. From 1908 to 
1911 varying numbers of individuals were immunized, first against 
typhoid, about sixty-three per cent, and later against paratyphoid 
A (forty-two per cent), and paratyphoid B (twenty-seven per 
cent). The disease steadily decreased during this period until 
the incidence of the three diseases reached the following figures 
per 100,000 in the vaccinated and unvaccinated (Kabeshima). 



180 TYPHOID FEVER 

TABLE XIX 

CASES OF THE TTPHOIDAL FEVERS IN VACCINATED AND IN VACCINATED MEN OF 
THE JAPANESE NAVY 

Typhoid Paratyphoid A Paratyphoid B 
Vaccinated 24 38 

Non- " 186 ^7 140 

THE GERMAN ARMY 

The general morbidity figures in Germany have been extremely 
low, reaching in 1912 something like three to the 100,000, and in 
Prussia, 1909 to 1910, eight to the 100,000, owing largely to the 
introduction of proper sanitation and the elimination of carriers 
(Kossel). 

The German Army has been relatively backward in adopting 
typhoid vaccination, particularly in view of the fact that the early 
scientific experiments on which the present methods are founded 
are due to Pfeiffer and Kolle. Vaccination, indeed, was not taken 
up seriously until the war against the Herreros (1904 to 1907), 
when the Government appointed a committee consisting of Koch, 
Gaffky, Kirschner, Donitz and Kolle to investigate its advisability. 
In the troops in Southwest Africa during the Herreros rebellion 
vaccination as recommended by this Commission was found to 
give distinct though only moderately successful results, as com- 
pared with results that were already being obtained elsewhere. 
Kuhn reports that in 7287 soldiers that were vaccinated the 
incidence was at the rate of 5100 per 100,000, with a mortality of 
330, whereas in 9209 non-vaccinated it was nearly twice as large, 
9900 per 100,000, with a mortality of 1260. It is further noted 
that the disease was much milder in the vaccinated and that the 
incidence varied distinctly with the number of injections that had 
been given. It is quite probable that the failure to obtain better 
results in these earlier campaigns was owing to the employment of 
the Pfeiffer-Kolle vaccine, which has since been shown in other 
hands to be of less immunizing value than other vaccines. The 
results in the present great war are largely a matter of guess work, 
although there is evidence that several different vaccines have 
been employed. For example, Goldscheider and Kroner speak of 
vaccination of the troops in 1914 with the Marx vaccine, whereas 
Sachs refers to the use of Kolle and Pfeiffer vaccine as a routine, 
with three injections. 

Considerable skepticism has been expressed in Germany during 
the present war as to the actual protective value of typhoid vac- 



THE PROTECTIVE VALUE OF VACCINATION 181 

cination (see, for example, Scholz and Hirsch), which seems 
extraordinary in view of the general acceptance of the method 
elsewhere. At all events, a considerable number of cases of the 
disease in the vaccinated have been reported (Mayer 2 and Bu- 
jioid). 

THE UNITED STATES ARMY 

The results obtained by typhoid vaccination in the United 
States Army have been widely and justifiably famous. The 
splendid results that have been achieved are attributable to the 
initiative of Major Russell, who, after the study of the conditions 
of antityphoid vaccination in England, introduced and was able 
to have compulsory vaccination enforced in July, 1911. Voluntary 
inoculation, as is shown by the accompanying table, was followed 
by a decrease in the number of cases, and compulsory vaccination 
by the almost complete disappearance of the disease. The results 
of the United States Army evidence not only the value of vaccina- 
tion in itself, but the value of having a body of men that is com- 
pletely vaccinated. Typhoid fever has not, however, absolutely 
disappeared even in the completely vaccinated troops, but vac- 
cination has reached a maximum of efficiency, which is astonishing. 

TABLE XX 

THE DECREASE OF TYPHOID FEVER IN THE U. S. ARMY FOLLOWING THE 
INTRODUCTION OF VACCINATION. (RUSSELL AND LYSTER) 

Cases per No. Vaccinated Army Strength 







100,000 






1901 


No vaccination 


674 






1902 


" " 


699 






1903 


" " 


514 






1904 


« << 


435 






1905 


" " 


314 






1906 


" " 


572 






1907 


" " 


379 






1908 


" " 


320 




74,692 


1909 


Voluntary 


335 


830 


— 


1910 


" 


243 


16,093 


81,434 


1911 


V2 compulsory 


85 


25,779 


82,802 


1912 


Compulsory 


31 


all 


88,478 


1913 


" 


4.4 


" 


90,752 


1914 


" 


7.5 


" 


92,877 



Eight cases of typhoid appeared in the army in 1915, four of 
which were in Hawaii, according to the Report of the Surgeon 
General, and it is evident from current reports that they are still 



182 TYPHOID FEVER 

occurring in the regular army.* The added danger of infection 
under conditions of actual warfare is suggested by the increase in 
number of cases during the summer of 1916, when large numbers of 
troops were concentrated on the Mexican border. Chamberlin 
reports that twenty-four cases occurred in regular and militia 
troops between May 1 and October 18 of this year. 

THE UNITED STATES NAVY 

The United States Navy employs the United States Army vac- 
cine, its use being obligatory in all enlisted men under forty-five 
years of age, with re-inoculation on every re-enlistment, that is to 
say, every four years. Since the introduction of vaccination the 
number of cases has dropped from an annual average in 1909- 
1911 of about two hundred to seventeen (1913-1915), according to 
the Annual Report of the Surgeon General, U. S. Navy, 1916. The 
few cases that have occurred in these later years have been almost 
entirely in those who had been vaccinated three or four years 
previously, and a shortening of the period before re-inoculation is 
under consideration. 

A certain number of failures in vaccination should be antici- 
pated in view of individual variations in reaction, and in the 
advent of greater exposure these failures are almost certain to 
increase. The method of vaccination in the American Army is 
practically the same as that employed in English troops, and has 
been carried out with an old English stock strain (Rawling's) ob- 
tained from Leishmann. The only innovation introduced was the 
addition of a third dose of vaccine which has since been adopted 
by other nations. One of the most important reasons for the 
remarkable success obtained in this large group of men over 
several years is undoubtedly due to the fact that they have con- 
stituted the first completely vaccinated aggregations, the impor- 
tance of which fact has already been referred to. 

A careful consideration of the results in the armies of the world 
which have to any extent employed typhoid vaccination shows 
conclusively the remarkable, and at times, wellnigh perfect pro- 
tective value of the method. The results, moreover, demonstrate as 
in the British Army where vaccination has been carried out for the 
longest period, that distinct improvements have been made in the 
method of vaccination, some of the reasons for which are clearly 
evident, as for example the adaptation of a method of killing the 
vaccine at lower temperatures and increasing the number or size of 
* See Military Surgeon, Feb. 1917, p. 240. 



THE PROTECTIVE VALUE OF VACCINATION 183 

the doses. Any comparison between the results obtained in one 
army with another is more difficult. It seems suggested at least 
that, apart from improvements in the killing of vaccines and 
dosage polyvalency, sensitization and other variations may 
affect the efficiency even more markedly. We have, for example, 
the observations of Ciuca, Combiescu and Balleanu, where it was 
found that Besredka's sensitized vaccine protected troops better 
than the Pfeiffer-Kolle vaccine. A similar tentative conclusion 
may be drawn from certain observations quoted by Vincent and 
Muratet that were obtained in the Italian Army,* where the 
morbidity rate in certain North African troops was shown after 
three injections of the Pfeiffer-Kolle vaccine to be 7.2 per 1000, 
whereas it was only three-tenths per 1000 when the same amount 
of Vincent's vaccine was used. 

We have already mentioned that the tendency has been to in- 
crease the number or size of the doses of vaccine employed. This 
increase in dosage has depended largely on army observation, and 
particularly on the relatively greater number of failures of typhoid 
vaccination with the small than with the large doses. Thus 
Goldscheider and Kroner found that of three hundred cases of 
typhoid among the vaccinated one hundred and twenty-five had 
had only one or two inoculations, whereas only thirty-nine oc- 
curred in the preponderating group that had received three in- 
jections. Similar results have been noted by Leger, Abt and 
Dumont and by Labbe\ 

A matter of considerable importance in the success of vaccinating 
armies depends, we believe, on the inclusiveness of the vaccination 
that has been obtained. It has already been suggested by Saw- 
yer 4 that the unusually successful results in the United States 
Army may have been due to some extent to the fact that the 
entire body of men was vaccinated. As corroborative of this 
point, we may mention that Widal 4 has shown that in certain 
groups of the French troops, where typhoid had been practically 
obliterated, it reappeared in spite of continued vaccination when 
fresh unvaccinated individuals were added to them at the begin- 
ning of the present war. It is further evidenced from the figures 
of Fleming that, as the English forces became more fully inocu- 
lated, the number of cases of typhoid among the inoculated de- 
creased as well as the actual number among the uninoculated, 
although, of course, the difference between the two was at all 
times very evident. Sergent and Negre find the incidence of 
typhoid among the few unvaccinated in the army remains low, al- 
* See p. 179. 



184 TYPHOID FEVER 

though relatively high among the adjacent civil population which 
is largely unvaccinated. In other words, the elimination of all 
foci of re-infection would, of course, tend to diminish the danger 
of exposure, which may result in typhoid even in the vaccinated. 

ANTITYPHOID VACCINATION IN INSTITUTIONS 

Vaccination against typhoid fever in insane hospitals and 
prisons has been very successful. This success again proves the 
efficacy of the method itself, because in institutions we have per- 
haps the most ideally controlled experiments available. Not 
only are some vaccinated and some left unvaccinated as con- 
trols, but those that are vaccinated are inoculated in a uniform 
manner, and both groups are subjected to almost identical dan- 
gers of contagion in so far as fixed residence can contribute to 
such stability. Among the successful results may be mentioned 
those reported by Hatchel and Stoner, 2 who found that in the 
institutions of Maryland, of 5512 individuals that had been 
vaccinated only three subsequently suffered from typhoid fever, 
a morbidity rate of fifty-eight to the hundred thousand, whereas 
the rates in previous years had been from five hundred to two 
thousand per 100,000. In the asylum at Braqueville Besredka 
reports that in 516 vaccinated individuals no case of typhoid ap- 
peared, whereas in 434 unvaccinated four cases occurred during 
the same period. The results, however, are by no means as uni- 
formly successful as those that have been quoted. Wade and 
McDaniel, for instance, in Minnesota found that in an asylum 
where carriers were subsequently proved to exist there were a 
considerable number of cases among the vaccinated as well as 
the unvaccinated, in spite of a positive Widal in the former, and 
they wisely suggest that vaccination alone is not sufficient to 
obliterate typhoid fever and that the protection following vac- 
cination must to some extent depend on the degree of exposure. 

VACCINATION AMONG PHYSICIANS AND NURSES 

Nurses and physicians probably undergo the maximum degree 
of exposure to typhoid infection. It has been estimated by Rich- 
ardson and Spooner that they are eight times as liable to the 
disease as the ordinary individual. Spooner has reported his re- 
sults with 1585 vaccinated nurses in Massachusetts with a mor- 
bidity rate of 150 per 100,000, whereas in 674 uninoculated in 
the same institutions the morbidity rate was 1190 per 100,000. 



THE PROTECTIVE VALUE OF VACCINATION 185 

Ogan has, on the other hand, reported a number of failures of 
vaccination among nurses and physicians exposed to a carrier. 
Some of the failures may have been due to the type of vaccine 
employed. Townsend found in Waterbury, Connecticut, that 
among eighty vaccinated nurses there were no cases of typhoid 
in a given epidemic, whereas four occurred among thirty-five 
unvaccinated. Elmer, again, cites instances in which practically 
the same number of cases occurred among the vaccinated as 
among the unvaccinated. In all matters of this sort where the 
results are found to vary, the more successful ones may be taken 
as indicative of what may be hoped for under milder conditions 
of infection or best conditions of vaccination, and the failures in 
certain instances are no reason for losing faith in the method. 

VACCINATION AMONG LABORATORY WORKERS 

Kisskalt has analyzed fifty cases of laboratory infection of ty- 
phoid fever, seven of which were in vaccinated individuals. Lab- 
oratory infections represent by all odds the most massive type 
of infection, as they are usually caused by swallowing cultures 
of the living microorganisms, which must represent relatively 
enormous infecting doses. Kisskalt would attempt to explain 
away failures of this sort on the basis of incomplete vaccination, 
weakness of the vaccine, and the like. It would seem to us much 
more reasonable to admit them frankly as failures of a method 
which could never be expected to be absolute and the success of 
which must depend on the usual hygienic observances, and again 
on the degree of infection that is undergone. We have already 
cited the instances of Marx and of Crombie, and may mention 
in addition the one of Auche and Chevaillier, which show clearly 
that typhoid may occur in completely vaccinated persons. 

RESULTS OF TYPHOID VACCINATION IN CIVIL COMMUNITIES 

Typhoid fever is not only a community but an individual 
problem, and the individual is therefore concerned in the benefit 
of typhoid vaccination as much as the group. The individual is, 
however, exposed to certain dangers of infection and protected 
from certain other dangers which may occur in armies or in in- 
stitutions. The severest trial of typhoid vaccination will for many 
years be among the general population, and failures will continue 
to occur among the vaccinated, and only in decreasing frequency 
with the increasing percentage of a community that is vaccinated. 



186 TYPHOID FEVER 

If the people would hasten the ultimate obliteration of the dis- 
ease, they might do so by being vaccinated, not when threatened 
with an unusual exposure to typhoid fever, but under the ordinary 
conditions of existence in which one is relatively protected in 
modern civilized communities. In spite of the occurrence of 
typhoid in the vaccinated, which, as we have stated, in general 
communities may actually exceed the normal rate, owing to the 
greater exposure, there are very well denned instances of strik- 
ing beneficial effect produced in small communities by this means. 
For example, Vincent 10 reports the results in the town of Paimpol, 
where four hundred individuals when threatened by an epidemic 
were vaccinated and subsequently developed no cases of typhoid, 
whereas two cases occurred in two unvaccinated families. Spooner 
reports equally interesting results in Greensboro, where sixty-five 
people were markedly exposed and seventeen had already suffered 
from the disease, and where of twenty-nine vaccinated individuals 
only one came down with the disease, whereas among nineteen 
uninoculated five cases developed. The results of Hatchell and 
Stoner in the general population, when compared with the 
success they obtained with physicians and nurses and in insti- 
tutions, bring out conclusively the results that may be ex- 
pected in general life. They have records of 7714 in the general 
population with a morbidity rate of 77.5, which, of course, mark- 
edly exceeds the rate for the state. A similar slight increase over 
the state morbidity rate has been shown by Sawyer in his com- 
parison of different types of typhoid vaccine in California. His 
figures would indicate a distinct advantage in the protective 
value of the Gay-Claypole sensitized vaccine sediment over com- 
mercial typhoid vaccines of the army type. Other instances of 
failure of typhoid vaccination in individual cases in civil com- 
munities have been noted by Gaither and many others. 

Estimation of the actual protective value will in this group of 
cases remain difficult, since, first of all, their number is indefinite, 
the methods of vaccination extremely variable, both in technique 
and in vaccine employed, and, finally, there is no strict control 
of the incidence in unvaccinated individuals under anything ap- 
proaching similar conditions of exposure. 

TYPHOID FEVER IN THE VACCINATED 

Much information has been gained concerning typhoid vac- 
cination, not alone from its successes but also from its failures. 
Of these, there have been a plenty during the great world war, 



THE PROTECTIVE VALUE OF VACCINATION 187 

and although it is impossible to consider them statistically in 
their entirety, the numerous facts that have already emerged 
are not only themselves of interest but will lead to a further un- 
derstanding of typhoid vaccination and to means of increasing 
its efficiency. Failures following typhoid vaccination may in 
many instances be explained by errors in the administration it- 
self, by too few vaccinations, or by improper vaccine, or, again, 
by the recent date of the vaccination, which must have antedated 
infection a sufficient number of days to ensure the maximum pro- 
tection that may be afforded. But there are a sufficient number 
of instances of real failures, where the individual has been vac- 
cinated at a properly antecedent date, where the full course in 
injections which is shown to produce protection in the majority 
has been given, and even where the presence of antibodies in the 
circulating blood has been demonstrated. As a concrete illustra- 
tion of true failures may be noted the cases of a physician described 
by Hueppe, 2 who in spite of three full courses of inoculations fell 
ill of typhoid fever. These true failures again illustrate the rela- 
tivity of any method of this sort, a conception fundamental to 
its full understanding. 

With the increase in the number of failures, which has occurred 
under the unusual opportunities for infection that have occurred 
in the great war, has come much information as to the underlying 
causes, and the failures should in no way bring a sense of dis- 
couragement with the method itself. We find that not only is 
antityphoid vaccination relatively protective, but that the failures 
themselves are relative and not absolute. Thus, it has been 
shown * that although the morbidity rate of typhoid fever in the 
French troops has actually risen from 1.88 per 1000 in 1911 to 
4.40 per 1000 in 1915, the mortality rate from this disease has 
fallen at the same .periods from 0.27 to 0.15. It should further be 
pointed out that under the heading of typhoid fever in such statis- 
tics are unquestionably included those cases of paratyphoid which, 
as we shall presently discuss, have in no way been abated by anti- 
typhoid vaccination, and have actually increased, as might be ex- 
pected, owing to. the greater danger of infection afforded in active 
service. These figures simply illustrate a truth, which has become 
more and more evident since the statistics of antityphoid vaccina- 
tion have accumulated, that the mortality among the vaccinated, 
as compared with the unvaccinated, decreases even more markedly 
than the morbidity, and it is, of course, with these ultimate re- 
sults that we are more concerned. We have already given illustra- 
* Editorial, Presse M6d., Feb. 17, 1916. 



188 TYPHOID FEVER 

tions of this relative reduction of mortality over morbidity, but a 
number of instances from the present war may be of interest, not 
only as bearing on the total morbidity and mortality rates from 
typhoid, but on the respective rates in the vaccinated and un- 
vaccinated. Bech found a mortality of sixteen per cent in his 
unvaccinated typhoid cases, whereas the rate in the vaccinated 
was 2.7 per cent. Bernard and Paraf had a mortality of 24.3 in 
the unvaccinated and 5.3 in the vaccinated. Donaldson and 
Clark had a mortality of fifteen per cent in the unvaccinated and of 
zero in the vaccinated. These figures taken from three of the 
greatest armies involved in the present war show very clearly the 
beneficial effects of typhoid vaccination even in those cases that 
from one aspect may be regarded as failures of the method. 

Not only is the mortality rate decreased in vaccinated individ- 
uals, who in spite of vaccination become infected with typhoid 
fever, but the disease itself is found to undergo a very distinct 
modification when it does occur in the vaccinated. It has fre- 
quently been found to be so mild as to offer great difficulty in its 
classification. Thus, Schlager has observed a mild type of fever 
in six per cent of his vaccinated men when they were exposed to 
infection, which he regards as typhoid in all probability. Bernard 
speaks of "Tembarras gastrique febrile," a typhoidal infection 
among the vaccinated, and Hirsch, 2 Frugoni, Goldscheider and 
Kroner, Meyer, Lampe, Olmer and many others speak of the 
extreme mildness of typhoid that may occur in spite of vaccina- 
tion. Sartori, Spillmann and Lasseur find that the disease in the 
vaccinated usually runs only ten to fifteen days. Goldscheider and 
Kroner note that the fastigium is either very brief or does not 
occur at all, the fever beginning in an abrupt manner and fre- 
quently aborting. Correlative with these findings are the ob- 
servations of Hohlweg, Labbe and Lampe that typhoid bacilli are 
found with less frequency in the circulating blood in the vac- 
cinated. Fewer complications are usually noted in the vaccinated, 
although it would seem that relapses are as frequent as in the 
unvaccinated (Hirsch, 2 Goldscheider and Kroner). 

We may, if we like, consider these failures of typhoid vaccination 
as suggesting the value of a polyvalent vaccine, for they have 
been attributed with a certain degree of circumstantial evidence 
by Vincent and Muratet to infection with an unaccustomed race 
of bacilli. 

Diagnosis of typhoid fever in the vaccinated is difficult, not only 
from the mildness of the symptoms which characterize it, but also 
from the fact that previous vaccination renders the ordinary 



THE PROTECTIVE VALUE OF VACCINATION 189 

method of diagnosis by agglutination tests difficult or impossible. 
We have already discussed the usual occurrence of agglutinins fol- 
lowing typhoid immunization and have further shown that the 
presence of a positive Widal is no insurance against infection with 
the typhoid bacillus. Such a positive reaction in cases of infec- 
tion, however, renders diagnosis difficult. Among the methods 
suggested for diagnosis of typhoid fever in the vaccinated by 
agglutination tests is the observation of a rising agglutinin titer on 
successive days in the suspected febrile individual (Seiffert; Alder- 
shof ; Hirsch 2 ). A constantly negative Widal, on the other hand, 
according to Courmont, Chattot and Pierret, tends strongly to 
rule out typhoid fever in a vaccinated individual. The assertion 
by Tidy that paratyphoid fever will cause the typhoid agglutinins 
to disappear has been amply disproved by the more extensive 
observations of Dreyer, Gibson and Walker. 2 According to Gar- 
bat, 2 a positive fixation reaction indicates typhoid fever rather 
than vaccination. Co-agglutination of Bacillus enteritidis is said 
to be present in typhoid fever but not in vaccinated individuals. 
The most certain method of diagnosis of typhoid fever, the isola- 
tion of the typhoid bacillus from the blood, is doubly valuable in 
detecting typhoid in the vaccinated. 

PARATYPHOID FEVER IN TYPHOID VACCINATED INDIVIDUALS 

The frequent occurrence of typhoidal fevers in vaccinated in- 
dividuals during the present world war temporarily, and in the 
absence of careful laboratory examination, was the cause of some 
discouragement as to the efficacy of typhoid vaccination. It has 
since, however, been found that the majority of such fevers are 
not true typhoid fevers due to the bacillus of Klebs and Eberth, 
but are caused in the majority of instances by one of the para- 
typhoid bacilli, or in another group of cases apparently by a type 
of coccus. We shall later consider the paratyphoid fevers, the 
importance of which has become more thoroughly appreciated by 
these observations, in more detail and confine our attention at this 
point simply to the existence and occurrence of paratyphoid infec- 
tions among those who have been vaccinated against typhoid. 

It seems definitely proven that under usual conditions typhoid 
fever is of more frequent occurrence than the paratyphoid fevers, 
not only in general communities, but in armies under the extreme 
conditions of exposure during war (Chantemesse). One of the 
most striking facts brought out by the observations in the present 
war has been that typhoid vaccination has little or no effect in 



190 TYPHOID FEVER 

preventing paratyphoid fever. This fact has been noted and 
agreed to by practically all the observers in the various armies (for 
example, Dreyer, Walker and Gibson, and Deve). It has been 
suggested, however, by Bernard, 2 and corroborated by Labbe* that 
typhoid vaccination may lower the mortality in paratyphoid fever, 
although it does not diminish its incidence. Labbe, for instance, 
finds that the mortality from paratyphoid in a series of 800 cases 
among those unvaccinated against typhoid was 11.5 per cent, 
whereas among the typhoid vaccinated it was reduced to 6.58 per 
cent. The frequent occurrence of paratyphoid in the typhoid 
vaccinated must have seriously affected and tended to increase the 
apparent failures in previous years, when diagnosis was based on 
purely clinical symptoms unsupported by blood cultures. The 
present war has shown very clearly that the ratio of typhoid to 
paratyphoid infections has been completely reversed as a result of 
typhoid vaccination. This has been shown to be true by the 
studies of Labbe and of Bauer, Abrami and Stevestre, Rist and 
many others. Bernard and Paraf, 2 for instance, have shown in a 
series of typhoidal cases in which careful blood cultures were 
taken that typhoid bacilli were isolated from thirty-two unvac- 
cinated cases, and paratyphoid bacilli from twenty-six similarly 
unprotected individuals. In typhoid vaccinated individuals in 
the same series, however, typhoid bacilli were found in only forty- 
five cases, whereas paratyphoid bacilli were found in 222. In a 
similar way Bech found that a series of 1521 blood cultures gave 
forty-seven per cent of positive results. Of these positive results, 
Bacillus typhosus was found to account for forty-four per cent of 
the infections in the non-vaccinated, but for only fourteen per 
cent of the infections in the vaccinated, whereas paratyphoid 
bacilli occurred in only seven per cent of the unvaccinated and in 
thirty-one per cent of the typhoid vaccinated. The evidence, 
however, distinctly is that there has been no absolute increase but 
rather a decrease of the typhoidal fevers, owing to typhoid vaccina- 
tion. In other words, the paratyphoidal fevers have increased 
relatively but not absolutely, and the total result would be a 
diminution of the entire group. Paratyphoid fevers were also a 
matter of considerable importance in the mobilization of the 
United States army on the Mexican border in 1916. Chamberlin 
states that there were 250 cases of this disease between May 1 and 
October 7, 1916, the majority of which were due to Bacillus para- 
typhosus alpha. The evidence is that in Europe, both the alpha 
and beta types have been present, the preponderance of one over 
the other varying with time and place; before the world war the 



THE PROTECTIVE VALUE OF VACCINATION 191 

infections reported were mostly of the beta type, but during the 
war both forms have been present. 

MULTIPLE VACCINATION 

The diminution of typhoid fever, then, as a result of vaccina- 
tion has led to disclosing and rendering more important the para- 
typhoid fevers. The paratyphoid fevers probably have always 
existed in equal numbers, but their importance has not been ap- 
preciated owing to a failure to differentiate them by laboratory 
methods from the typhoid fevers, and also owing to the former 
preponderance of true typhoid fever. It was suggested by Cas- 
tellani in 1905 (Widal 4 ) that vaccination, particularly of troops, 
to be most effective should consist in immunization not only 
against typhoid fever but against the paratyphoid fevers by the 
use of a triple vaccine compounded of the three specific organisms. 
The results in the present war have led to a warm support of 
this suggestion by practically all observers (Landouzy; 2 Dreyer, 
Walker and Gibson; 3 Leger, Abt and Dumont). Leishmann is 
practically the only one who has not been enthusiastic about the 
use of triple vaccine, owing to the fact that he has not regarded 
the number of cases as sufficient or the seriousness of the disease 
great enough to warrant this additional vaccination. There 
would appear to be no contraindication to such a measure on 
the ground of vaccination symptoms. A triple vaccine containing 
in all actually more bacteria apparently produces no more severe 
reactions^than does the simple typhoid vaccine, according to the 
results of Kabeshima, Dreyer, Walker and Gibson; 3 Widal and 
Courmont; and Widal. 5 The usual dosage that has been recom- 
mended for such a triple vaccine has been 500 million typhoid 
bacilli and 250 million each of the two paratyphoid organisms. 
Widal 6 suggests employing equal amounts, and in collaboration 
with Salimbeni has found that a relatively large dose of mixed 
vaccine may be given in two doses, which together include ten 
billion bacteria, without serious effects. 

It has been shown by several observers, notably by Widal and 
Sicard, by Castellani, 3, B and by Kabeshima, that injection of a 
triple vaccine of typhoid and paratyphoid bacilli will give rise 
to antibodies active against each of the organisms in question, 
and each one quite as strong as if a single organism had been 
employed. The first results from the use of this triple vaccine 
are probably those reported by Kabeshima, who states that the 
method has been in use in the Japanese navy since 1908 and that 



192 TYPHOID FEVER 

striking diminution of all three of the diseases has been produced 
by this means. Reference has already been made to his report 
on page 179. Castellani recommended the method in 1905 and 
has reported on results extending as far back as 1909. 6 * 8 Vin- 
cent 6 also was one of the first to recommend the use of a triple 
typhoid-paratyphoid vaccine, and at his suggestion the method 
was utilized in the Italian army in 1912 and in the French armies 
in Morocco in 1913 and 1914, with extraordinary good results. 
It may, then, be taken as a foregone conclusion that the use of 
paratyphoid vaccine, administered simultaneously with typhoid 
vaccine, will eventually lead to the decrease and disappearance 
of paratyphoid fever as well as of typhoid fever. Davison states 
that the use of a triple vaccine has been made compulsory in the 
British army since January, 1916. 

Multiple vaccines of other sorts have been suggested, and to 
some extent employed in troops and individuals who might be 
exposed to several infections, particularly in the tropics. Thus, 
Castellani 9 has employed a vaccine containing not only typhoid 
and paratyphoid bacilli, but also plague bacilli and the spirilla 
of Asiatic cholera. Another vaccine which he has recommended 
includes the causative organisms of Malta fever and of dysentery. 
The use of different combinations of this type would, of course, 
depend upon the existing diseases in the locality in which the 
inoculated individual lives. Johnson and Milne have utilized a 
typhoid vaccine with the addition of dysentery bacilli, but find 
that the latter organisms must be sensitized in order to diminish 
the severity of reactions which they would otherwise cause. 

DURATION OF THE PROTECTION AFFORDED BY ANTITYPHOID 
VACCINATION 

One of the most important questions to be considered in any 
systematic attempt to apply typhoid vaccination is the duration 
of protection that may be expected from any given method em- 
ployed. Estimates of this duration have rested largely on the 
accumulation of statistical evidence as to the tendency of fail- 
ures to occur after a certain lapse of time following inoculation. 
Firth, to whom we owe the most careful statistics of this sort, 
estimated that the protection following the type of inoculation 
carried out in the British army in India tended to disappear 
rather sharply after thirty months. In other words, the duration 
of immunity might be assumed in the majority of troops treated 
in this manner to last some two and one-half years. These figures, 



THE PROTECTIVE VALUE OF VACCINATION 193 

although representing an accurate mean for the group, give little 
information as to the duration of protection assured in the in- 
dividual case. The duration would differ, moreover, in accord- 
ance with the method of inoculation employed, since some methods 
are recognized to afford longer protection than others. Cas- 
tellani 1 thinks that the ordinary methods of typhoid immuniza- 
tion may be expected to last for one or two years. Kossel also 
estimates that typhoid immunity lasts from one to two years. 
Others have suggested that protection may last for five years or 
more.* In the United States army and navy it has been assumed 
that re-vacci nation would be required only once in four years. 
In the French army Vincent has recommended re-vaccination 
every year. It is evident, then, from these figures that we have 
no accepted standard by which we may judge when re- vaccination 
is indicated on the average and when it should be applied in large 
groups of men. Of still greater importance is the question of 
individual protection, for we recognize from the failures that 
may occur at any period subsequent to typhoid vaccination, 
even in a few weeks, that certain individuals fail to respond suf- 
ficiently to be protected against the ordinary chance of in- 
fection. 

Statistics are of no avail in assuring anyone that he or she is 
not protected against typhoid fever as the result of a previous 
vaccination, or should not be re-vaccinated in order to give greater 
assurance. We have already discussed in detail the inadequacy 
of estimating the agglutinin titer either in animals or in human 
beings as a measure of resistance against infection by the typhoid 
bacillus. We have seen on the one hand that those individuals 
best protected against typhoid infection, the typhoid recoveries, 
usually soon give a negative Widal test, and that men and ani- 
mals with lower agglutinin titer, as for example after the use of 
sensitized vaccines, are often better protected than those with a 
higher titer. On the other hand, we have noted that the ma- 
jority of typhoid vaccinated individuals show a positive Widal, 
which is usually higher than the ordinary typhoid recovery (Dryer, 
Gibson and Walker 3 ), and yet such individuals are by no means 
invariably protected against typhoid fever, and individuals that 
gave a positive Widal a few days before infection have been de- 
scribed. We cannot, then, rely upon the determination of anti- 
bodies as usually estimated for indication as to the degree or the 
duration of protection afforded by antityphoid vaccination. 

In an effort to devise a reaction of significance as indicating 
* Editorial, Jour. Am. Med. Asso., July 22, 1916, p. 285. 



194 TYPHOID FEVER 

resistance against typhoid fever, Gay and Force were led to de- 
velop the typhoidin test, the results with which have already been 
described in individuals that have recovered from typhoid fever. 
We have already mentioned that this test of localized hyper- 
susceptibility to products of the typhoid bacillus has been accept- 
ably proven to be positive in the majority of cases of recovered 
typhoid fever and negative in the majority of normal individ- 
uals. 

The typhoidin test in vaccinated individuals has been found 
in the hands of Gay and Force, Gay and Claypole, 3 Mehler, 
Pulay, Force and Stevens, and Gay and Lamb to be for the most 
part positive, the percentage of positive reactions, in general, 
diminishing directly with the duration of the time that has elapsed 
since vaccination. In other words, they diminish with the known 
conditions which tend to the disappearance of resistance. There 
are a number of other facts which have led us to regard the ty- 
phoidin test with increasing confidence as an indication of im- 
munity from typhoid fever. In the first place, the typhoidin 
reaction not only occurs in a higher percentage of typhoid re- 
coveries than in typhoid vaccinated, but usually occurs with 
greater intensity in the first than in the second category (Pulay, 
Force and Stevens). The typhoidin test, although negative in 
normals will become positive in those same individuals after a 
course of antityphoid injections (Force and Stevens). On the 
re-vaccination of people who give a positive typhoidin test, the 
reaction to the typhoid vaccine is more marked, as is also the case 
in typhoid recoveries. The typhoidin test does not occur im- 
mediately after the termination of a series of inoculations, nor 
does it occur usually during the course of typhoid fever. In other 
words, it tends to occur when a condition of relative resistance 
has been established. The typhoidin test is frequently not found 
positive until a month after the end of treatment, which corre- 
sponds to the greater percentages of failures of typhoid vaccina- 
tion immediately following inoculation. 

A certain number of individuals even after the completion of the 
usual course of prophylactic inoculations give repeated negative 
typhoidin tests. This, we believe, may be correlated with the 
cases of failure which may occur even at the time when immunity 
is usually strongest. Of further suggestive value is the fact that 
typhoid fever has occurred in our experience in three vaccinated 
individuals in whom the typhoidin test was negative or doubtful, 
whereas infection has never so far occurred in the very considerable 
number of cases in which we have found the reaction positive. 



THE PROTECTIVE VALUE OF VACCINATION 195 

As further indicating the prognostic value of the test, is the fact 
that a subsequent injection of typhoid vaccine will usually 
cause such a negative individual to give a positive test, thus agree- 
ing again with the greater protection recognized to be afforded by a 
larger number or larger total amounts of vaccine. 

One of the most interesting facts is the relation of the per- 
centages of negative typhoidin tests, which occur at successive 
periods subsequent to vaccination, to the condition found on re- 
vaccination against small-pox.* A successful re-vaccination in 
small-pox, of course, indicates that the immunity of the individual 
has run out, in other words, that that individual is not protected 
against small-pox, and a successful re-vaccination, therefore, 
would correspond to a negative typhoidin test, if we may assume 
that both are indications of lack of resistance to the respective 
diseases in question. In the following table are shown, first of all, 
the increasing percentage of negative typhoidin tests which occur 
in successive years following antityphoid inoculation, and in 
parallel columns are listed the corresponding successful small-pox 
re-vaccinations obtained by Kitasato and Lescohier. The paral- 
lelism is certainly too striking to be accidental, and would unques- 
tionably indicate a similar condition in the two instances, and 
furthermore tend to prove that the typhoidin test is really a 
measure of the degree of immunity to typhoid fever, whether ac- 
quired by recovery from the disease or by artificial immunization 
against it. 

TABLE XXI 

RELATIONS OF PREVIOUS TYPHOID VACCINATION, ON THE ONE HAND, TO THE 
PERCENTAGE OF SUBSEQUENT NEGATIVE TYPHOIDIN TESTS (FORCE AND 
STEVENS; GAY AND LAMB), AND, ON THE OTHER, OF PREVIOUS SMALL-POX 
VACCINATION TO SUCCESSFUL RE-VACCINATION (KITASATO; LESCOHIER) 

Time Since Typhoidin Negative Small-pox Re-vaccination 
Vaccination F. & S. G. & L. Positive 









K. 


L. 


1 year 


27 


36 


14 


28 


2 years 


45 


36 


33 


33 


3 " 


50 


46 


47 


58 



For greater emphasis it may be re-stated that the object of this 
test as proposed by Gay and Force was not a method of insurance 
against infection with the typhoid bacillus, which certainly could 
never be given, not even following recovery from typhoid fever, but 
asan indication of a lack of resistance, which is quite another 

* I am indebted to Dr. J. N. Force for calling this matter to my attention. 



196 TYPHOID FEVER 

thing, and which serves a useful purpose in designating the partic- 
ular individual that at any given time may require re-vaccination. 
In the voluntary immunization of students at the University of 
California it has been customary to request return a month after 
vaccination for a typhoidin test. If the test is negative, one or 
more further injections of vaccine are given. They are then 
urged to return at least every two years for a subsequent test, 
which when negative is taken to indicate need of another course of 
injections. 

A further word may be said in reference to non-specificity in the 
typhoidin test. Nichols has found that some sixty-six per cent 
of the seventy-five per cent of typhoid vaccinated in his expe- 
rience that gave a positive typhoidin test would also give a posi- 
tive test to paratyphoidin alpha, and he very correctly remarks 
that recovery from typhoid or vaccination against typhoid af- 
fords no protection against paratyphoid. It is questionable 
whether Nichols' results would have been obtained if he had 
followed the forty-eight hour observation which we have since 
found to be more correct, and if he had used the intradermal 
method of testing. We ourselves have found in a certain number 
of cases that typhoid recoveries gave positive paratyphoidin re- 
actions by the earlier cutaneous test, but almost invariably much 
less marked reactions to paratyphoidin than to typhoidin, the 
single exceptions being cases of authenticated paratyphoid fever. 
In other words, it is probable that a quantitative difference in the 
paratyphoidin reactions in typhoid recoveries could readily be 
demonstrated. But, even supposing these group reactions to be 
present, such results could not be taken as invalidating either 
the fact that a positive typhoidin test is an indication of relative 
protection, and certainly not as invalidating the only conclusion 
on which we wish to insist, that a negative test is an indication for 
re-vaccination. 

One point remains to be mentioned before terminating our dis- 
cussion of antityphoid immunization: that is, whether or not 
vaccination is to be recommended as a procedure during the incuba- 
tion period of the disease, as when an individual is actually known 
to have undergone or been exposed to infection. Authorities 
apparently differ markedly on this subject. Thus, Hirsch 2 and 
Camrraert regard vaccination in the incubation period as leading 
to a negative phase and increasing the incidence of severe cases. 
The majority of observers, however, would either attribute no 
effect to such vaccination, as, for example. Elmer, or would regard 
it of very distinct benefit, as do Chantemesse, Vincent, 7 and 



THE PROTECTIVE VALUE OF VACCINATION 197 

Davis. Haibe, Vincent, 8 and Noack cite cases in which vaccina- 
tion was promptly begun, following known laboratory infection 
with no resulting symptoms of disease. They are not, however, we 
believe, justified, owing to the absence of proper controls, in re- 
garding the treatment in these cases as having actually prevented 
the disease. 



CHAPTER XII 
THE PARATYPHOIDAL INFECTIONS 

There exists a group of human maladies closely allied to ty- 
phoid fever both in their clinical manifestations and in their 
respective causative agents. These paratyphoidal infections, as 
they are called, present themselves in each and all of the forms of 
disease in which typhoid fever occurs, although with different 
relative frequency. We find localized infections such as abscesses, 
meningitis and cholecystitis, paratyphoid bacteremia or para- 
typhoid fever, and gastro-intestinal infections comprising gastro- 
enteritis and cholera nostras. Until the advent of systematic 
bacteriological examination of the blood and feces, the more 
generalized infections of this group were classed, respectively, as 
food poisoning, cholera nostras, and authentic typhoid fever. 
The paratyphoid infections are caused by a group of microor- 
ganisms lying intermediate between Bacillus coli and Bacillus 
typhosus. The majority of these intermediate forms are more 
like the colon bacillus in cultural characteristics and in pathogenic 
properties; they differ from the typhoid bacillus not so much in 
their pathogenicity for man as in their superior pathogenicity for 
animals. Certain of the bacteria of the paratyphoid group affect 
animals only, so far as is known; others both man and animals; 
and still others of the group lying nearest biologically to the ty- 
phoid bacillus resemble the latter organism in producing only 
human infections. 

We are primarily concerned here with the paratyphoid infec- 
tions of man, and more particularly with that tj^pe of human 
paratyphoid that resembles typhoid fever most closely. No proper 
appreciation of human paratyphoid infections can be gained, 
however, without a survey of the paratyphoid group of bacteria 
in general, whether primarily pathogenic for man or animals. 
The presentation of the exact relationship between human and 
animal diseases in this group is difficult not only owing to their 
relatively considerable number but to our ignorance of the exact 
biological relationship between their respective causative micro- 
organisms. A schematic presentation of the more important 
bacteria of this group in relation to disease may be introduced at 

198 



THE PARATYPHOIDAL INFECTIONS 



199 



this point to facilitate discussion. The following table (Table 
XXII) is drawn largely from the complete and recent treatise of 
Uhlenhuth and Hiibener. 





TABLE XXII 




GENERAL RELATIONS OF BACTERIA OF 


THE INTERMEDIATE 


OR PARATYPHOID 




GROUPS TO HUMAN AND ANIMAL DISEASE 




Microorganism 


Animal Infections 


Human Infections 


Organism 
First Described 


Salmonella Group 








B. paratyphosus B. 


Primary or secondary 
septicemia in cattle 
and horses. Present 


1. Gastro-enteritis; 

2. Choleriform disease; 

3. Typhoidal bacte- 


Achard & Bensaud 
1896 




in intestines of 
normal animals 


remia; 
4. Local infections 




B. cholerae suia 


Secondary invader in 
hog cholera 


'- 


Salmon & Smith s 
1885 


B. typhi murium 


Epidemic enteritis 
and septicemia in 
mice 


Gastro-enteritis; 
Typhoidal bac- 
teremia 


Loffler* 

1890 


B. icteroides 





Secondary invader 
in yellow fever 


Sanarelli 2 

1897 


B. psittacosis 


Epidemic enteritis 
in parrots 


Typhoidal disease 
Pneumonia 


Nocard. 1892 


Various bacilli. 

Some of this group 


Dysentery and septi- 
cemia in calves 








B. nodulifaciens 


Localized liver ne- 
croses in calves 





Langer. 1904 


Gaertner Group 








B. enteritidis 


Septicemia, enteritis, 
or mastitis in cattle 


Gastro-enteritis 
(Food poisoning) 


Gaertner. 1888 


B. danysz 


Epidemic enteritis and 
septicemia in rats 
and mice 





Danysz. 1900 


B. paratyphosus A 





Typhoidal bacteremia; 
Typhoidal local- 
ized lesions 


Gwyn. 1898 









It appears from this table that the more important micro- 
organisms classified under the general heading of paratyphoid 
bacilli may be divided into three general groups. These groups 
have been separated on the basis of cultural and immunological 
characteristics, to which we shall later refer. 

Group I consists of those organisms which have been classified 
under the general heading of the hog cholera group or salmonel- 
loses, a name given by Lignieres in deference to Salmon, who with 
Smith described the first member of this group in 1885. 

Group II comprises two organisms, the Bacillus enteriditis of 
Gaertner and the bacillus of Danysz. 

Group III contains Bacillus paratyphosus alpha. 



200 TYPHOID FEVER 

As we shall later see, separation between the first and third 
groups or their type organisms, Bacillus paratyphosus beta and 
Bacillus paratyphosus alpha, is easy on the basis of both con- 
stant cultural and immunological differences. The separation 
between organisms of the hog cholera group and of the enteritis 
group is by no means so easy. Individual members in these 
groups differ culturally, but there is no constant cultural differ- 
ence which would make it possible to place a new organism in 
one group rather than the other. By means of absorbed specific 
immune sera, however, it may be shown that constant differences 
really exist between the two groups. All of the organisms con- 
sidered under these three headings lie biologically intermediate 
between the colon bacillus and the typhoid bacillus, the hog 
cholera group of organisms being most like the colon bacillus, 
and the paratyphoid alpha organism being very close to the 
typhoid bacillus. These relations are maintained on immunolog- 
ical grounds as well as through cultural characteristics. Similar 
differences between the organisms at the two extremes are like- 
wise evident in their respective pathogenic properties. The 
colon-like organisms differ from the typhoid bacillus and the 
paratyphoid alpha bacillus in that they are not only experimen- 
tally more pathogenic for animals, but produce spontaneous dis- 
ease in them, particularly in cattle, in the nature of enteritis and 
septicemia. These animal diseases may occur in epidemic forms, 
as in the case of calf dysentery, mouse typhoid, and the psittacosis 
of parrots; or they may be secondary septicemias, as in the case 
of hog cholera. The microorganisms further produce localized 
inflammatory, purulent, or necrotic processes, as in the case of 
Bacillus enteriditis, which produces mastitis in cows, and the 
bacillus nodulifaciens, which is the cause of localized liver necrosis 
in calves. 

In man the colon-like organisms are less frequently the cause 
of disease than the true typhoid bacillus, and the diseases they 
do produce in man are more frequently similar to the animal 
diseases than to true typhoid fever. Human infections may be 
produced by the colon-like organisms in the form of enteritis, 
which is, properly speaking, an intoxication and often so severe 
as to be choleriform in nature, or else in the form of a true infec- 
tion resembling typhoid fever; or, again, as with the typhoid 
bacillus, in the form of localized lesions such as pyelitis, cystitis, 
meningitis, appendicitis, cholecystitis, and pneumonia (Bacillus 
psittacosis). 

The paratyphoid alpha bacillus is not only culturally very 



THE PARATYPHOIDAL INFECTIONS 201 

close to Bacillus typhosus, but resembles it in its pathogenic 
properties. So far as is known, it does not produce a spontaneous 
disease in animals, and the human infection which it causes is 
an infection like typhoid fever. 

We are concerned in this treatise primarily with the bacteremia 
of typhoidal type, which several of these intermediate organisms 
may produce. The paratyphoidal fevers, first of all, resemble 
true typhoid fever in practically all particulars; secondly, they 
present certain interesting problems of transmission which differ 
from the characteristic modes of transmission in true typhoid; 
thirdly, the paratyphoidal fevers are of interest in connection 
with the problem of immunization against typhoid, since, as we 
have already shown, protection against the one disease does not 
offer security against the other, although the same method ap- 
plied in paratyphoid that has been utilized in typhoid will doubt- 
less produce similar successful results; and, lastly, the paraty- 
phoidal fevers are found of increasing importance owing to the 
information that has been gained of their distribution and prev- 
alence in the present world war. 

The more characteristically paratyphoidal type of human in- 
fections, the gastro-enteritis, also finds its analogy in certain 
forms of true typhoid fever, as we have already mentioned. Cer- 
tain of the milder forms of typhoid fever, as for example the 
French "embarras gastrique febrile" and the mild intestinal 
upsets occurring in children due to this organism, are cases in 
point. The choleriform type of paratyphoid infections is more 
strictly characteristic. Localized infections occur in perhaps 
greater frequency with the paratyphoid infections than in true 
typhoid, although in no characteristically different situations. 

Our discussion of the relation of paratyphoid infections to 
typhoid fever narrows itself not only to consideration of the 
bacteremic type of paratyphoid infection, but also to the par- 
ticular consideration of only two of the microorganisms men- 
tioned as the cause of human or animal disease. We shall con- 
cern ourselves largely with a discussion of Bacillus paratyphosus 
alpha and Bacillus paratyphosus beta in their relations to the 
true typhoid bacillus. These two paratyphoid organisms pro- 
duce the majority of human paratyphoid bacteremias. Excep- 
tions, however, should be allowed in this statement and will 
probably increase with greater frequency as our ability to dif- 
ferentiate the causative microorganisms increases. A number of 
forms of paratyphoid bacilli intermediate between the alpha and 
the beta type have been described, as for example in recent years 



202 TYPHOID FEVER 

the organism isolated by Ohno, the bacteria described by Sar- 
railhe and Clunet, 2 which produced an epidemic in the Dar- 
danelles, and the organism described by Daumezon. Other closely 
related organisms, as Bacillus fecalis alkaligenes, have also been 
found to give rise to generalized typhoidal infections. A further 
group of infections of this nature, due apparently to a micrococcus 
(M. typhoideus), have been described by Sartori, Spillman and 
Lasseur, and by Bourges, Lancelin and Jolly. 1, 2 In considering 
the general infections due to members of the paratyphoid group 
of bacteria, it should be mentioned that not only may any one 
of the organisms be the cause of a disease, but that a mixed in- 
fection of typhoid and paratyphoid may occur, as in the cases 
reported by Gerard and Fenestre, and by Castellani. 10 



CLINICAL DIFFERENTIAL DIAGNOSIS OF PARATYPHOID FEVER 

It seems certain from our present knowledge that no differen- 
tiation between the paratyphoid fevers and typhoid fever was 
made before the era of bacteriological examinations, although 
claims to the recognition of such a form of disease separate from 
typhoid have been made in retrospect by some observers. With 
the increasing body of information that has come, particularly 
in the last few years, in respect to cases of paratyphoid fever 
that have been authenticated by bacteriological analysis, it ap- 
pears that certain minor clinical differences between paratyphoid 
and typhoid fever may be noted. Although fairly consistent 
for the paratyphoid group in general, these differences are not 
any greater than might occur between individual cases of ty- 
phoid fever, and could certainly never be used for the purpose 
of differential diagnosis of the one disease from the other in any 
given case. Fortunately, differential diagnosis is not primarily 
essential, except in so far as recognition of the relative importance 
of paratyphoid fevers is concerned, and in the elaboration of 
specific measures of prevention. As far as the individual case is 
concerned, the treatment and prevention of extension of the dis- 
ease is the same in paratyphoid as in typhoid fever. 

The main points of differentiation between paratyphoid and 
typhoid fever have been repeatedly emphasized by the recent 
work, principally of French observers, during the war conditions 
in Europe. In general, the paratyphoid fevers are less severe 
infections than typhoid. The initial symptoms of paratyphoid 
fever resemble typhoid closely and are characterized by insomnia, 
headache, epistaxis and nausea. The onset of the disease in para- 



THE PARATYPHOIDAL INFECTIONS 203 

typhoid is more frequently abrupt than in typhoid, and is often 
accompanied by vomiting and by chills. The gastro-intestinal 
symptoms in general in paratyphoid are more marked through- 
out the disease than in typhoid fever. The temperature in para- 
typhoid usually rises more sharply than in typhoid, has a shorter 
fastigium, and is in total duration notably less on the average 
than is the case in typhoid fever, the disease usually being under 
two weeks in duration. 

Severe occipital pain is a common symptom in paratyphoid. 
Dicrotism of the pulse is less frequent than in typhoid. Herpes, 
both about the lips and in the mouth, are of characteristically 
frequent occurrence. The mental condition in paratyphoid 
usually fails to show the characteristic typhoidal state, although 
meningeal involvement is more frequent than in the true typhoid 
fever. The liver is more enlarged in paratyphoid, but the spleen 
less notable than in typhoid fever. Jaundice is a frequent symp- 
tom and may occur as the predominating symptom in certain 
epidemics (Sarrhailhe' and Clunet). Sweating is frequent in 
paratyphoid, and the rose spots distinctly more frequent in oc- 
currence than in typhoid fever. They were found by Robinson 
in sixty per cent of his cases, and may become confluent and 
even persist after apyrexia. 

The complications of paratyphoid differ only in relative propor- 
tion from those in typhoid. In general, recent work has shown 
that complications may be as frequent and severe as in true ty- 
phoid fever; for example, Nobelcourt and Peyre found com- 
plications in 38.8 per cent of their paratyphoid alpha cases, in 
thirty per cent of the typhoid cases, and in 23.6 per cent of the 
paratyphoid beta cases. As already mentioned, meningitis is not 
infrequently observed (Sacqu6pee, Burnet and Weissenbach; 
Tolmer and Weissenbach; Daumezon -). Hemorrhage occurs in 
five to six per cent of cases. Phlebitis (Minet), pyelitis (Korezyn- 
ski), epididymitis (Giroux), and myocarditis have recently been 
emphasized as of relatively frequent occurrence. Peritonitis may 
occur with or without perforation. Perforation itself is appar- 
ently as frequent as in typhoid fever. Relapses occur as fre- 
quently as in true typhoid. Thus, Rimbaud, and Coyon and 
Rivet had relapses in ten per cent of their cases. 

Previous to the present war conditions the mortality from para- 
typhoid fever was extremely low, although the number of cases 
which serve as a basis of comparison was extremely small. Esti- 
mates as low as one per cent of mortality have been given by va- 
rious authors. More recent work would tend to show that the 



204 TYPHOID FEVER 

mortality from paratyphoid, although lower than from typhoid, is 
somewhat higher than has generally been assumed. LabbeY' for 
example, had a mortality of five per cent with paratyphoid and of 
twenty-five per cent with typhoid, and in a later series 3 a closer 
correspondence of eleven per cent for paratyphoid and fifteen per 
cent for typhoid. The total mortality due to the two diseases 
during the present war has, of course, been diminished by anti- 
typhoid vaccination, which has sharply decreased not only the 
incidence but the percentage mortality in true typhoid. 

The pathological anatomy of paratyphoid fever as compared 
with typhoid is interesting and somewhat characteristic. In the 
earlier cases that came to autopsy, as for example the one de- 
scribed by Longcope, 3 no lesions were found in the intestine 
suggesting typhoid fever. Later and more extended observations, 
particularly in recent years, have shown that the lesions char- 
acteristic of typhoid may also be produced by the paratyphoid 
infections, although in general the lesions in paratyphoid would 
seem to extend indiscriminately to the solitary follicles as well as 
to the agminated follicles of Peyer in the small intestine, and in a 
recent series of cases have been found in the colon as well (Sacqul- 
pee, Burnet and Weissenbach; Grenet and Fortineau). The 
spleen, as noted under the clinical characteristics, is swollen, 
although not so markedly as in typhoid. 

THE LABORATORY DIAGNOSIS OF PARATYPHOID FEVER 

Significant and characteristic as are these clinical variations of 
paratyphoidal infections from true typhoid fever when cases are 
viewed in aggregate, they offer little security in the diagnosis of 
any particular case of a disease of this type. A differential diag- 
nosis of paratyphoid infection depends, as in the case of typhoid 
fever, on laboratory examinations. The paratyphoid bacilli are 
found in instances of the disease which they cause, very much as is 
the typhoid bacillus in typhoid fever, that is to say, in the blood, 
the stools and the urine. In the case of localized lesions the or- 
ganism will, of course, be found in the affected locality. 

At this point it may be well to refer briefly to the historical 
evidence on which our present conception of the bacteriology of 
human paratyphoid infections is based. First, to mention two of 
the paratyphoid organisms, which, although not concerned with 
the type of human infection we are primarily considering, are yet 
of historical interest as giving a basis of classification for subse- 
quently isolated microorganisms. Salmon and Smith described 



THE PARATYPHOIDAL INFECTIONS 205 

the hog cholera bacillus in 1885, an organism which they found 
constantly in the intestines of swine dead of the disease in question, 
and which at that time was supposed to be the causative agent in 
the disease. It has subsequently been shown that it is a secondary- 
invader and that the real cause of hog cholera is a filterable virus. 
In 1888 Gaertner isolated an organism (Bacillus enteritidis) from 
diseased beef and from the intestinal contents of fifty-seven cases 
of meat poisoning that had been caused by eating this contam- 
inated food. 

In 1896 Achard and Bensaud isolated an organism, which they 
denominated Bacillus paratyphosus, from the localized lesions 
subsequent to supposed attacks of typhoid fever in two human 
beings. This organism has since been shown by subsequent 
comparative studies to be identical with Bacillus paratyphosus 
beta. Gwyn in 1898 isolated an organism from the blood in a case 
of typhoidal disease which differed from the typhoid bacillus in 
certain particulars and was agglutinated by the patient's serum, 
which serum failed to agglutinate a true typhoid bacillus. This 
organism he named Bacillus paracoli, although subsequent exam- 
ination showed that it is identical with the organism subsequently 
differentiated as Bacillus paratyphosus alpha. In 1900 Schott- 
muller 2 in his study of the bacteriology of typhoid described five 
cases from which he isolated organisms that differ from the true 
typhoid bacillus. He further separated these paratyphoid or- 
ganisms into two groups, which subsequent study has shown to be 
the alpha and beta groups that we have discussed. 

Blood Cultures in Paratyphoid Cases 

Blood cultures are of preeminent value in the diagnosis of 
paratyphoid infections as in true typhoid fever, and are made in 
the same way. The organisms are somewhat more difficult to 
obtain in paratyphoid cases, owing to the fact that they are 
present in the circulating blood for shorter periods of time than 
in typhoid fever. On first examination of blood cultures in para- 
typhoid infections the organisms present, motile, plump, Gram- 
negative rods, give no differential indication of whether one is 
dealing with typhoid or paratyphoid bacilli. The identification 
remains for subsequent examination, as will be described. Stool 
cultures are also made in a similar way to cultures in typhoid 
fever, and the paratyphoid colonies are not markedly different 
from typhoid colonies on the more important differential media, 
Endo or Conradi-Drigalski, for example, but may be sharply 



206 



TYPHOID FEVER 



differentiated from the colon organisms, for which purpose these 
media are devised. 

TABLE XXIII 

DIFFERENTIAL BACTERIOLOGICAL CHART 



Odor 

Motility 



Broth 
Potato (acid) 



Artichoke 
Litmus milk 



Lactose 1 
Raffinose \ 
Saccharose J 
Glucose 
Levulose 
Maltose I 
Galactose [ 
Duloite 
Mannite J 
Neutral red > 
Glucose agar ) 
Na sulphite 

fuchsin (Endo) 
Lit. lactose 

crystal violet 
(Conradi- 

Drigalski) 
Suhacetate of 

lead 
Indol 



B. Typho 



Not significant 

Motile 

No pellicle 
Moist, glistening. 

brownish, not 

vcrv visible 
No change in 

color 
Slight acidity 



No acid. No gas 
Acid. No gas 

No change 

Colonies colorless 
Blue, transparent 

Blackened 
No 



8. Paratypltosus A B. Paratyp', 



Slight 

Motile 

Pellicle 

Moist, glistening, 
not very visible 

Little or no 

change in color 
Slight acidity 



No acid. No gas 



Decolorized flu- 
orescence. Gas 

Colonies colorless 

Blue, transparent 

Not blackened 
No 



Fecal. Disagree- 
able. 
Motile 

Pellicle 

Thick, brownish, 
sometimes scanty 

Green in 2 or 3 
days 

Sliyht acidity, 
then alkaline. 
Ammonia formed 

No acid. No gas 



Decolorized flu- 
orescence. Gas 

Colonies colorless 

Blue, transparent 

Blackened 

No 



Fecal 

Usually but not 
oli ays motile 

Pellicle 

Projects; yel- 
low or brown- 
ish 
Green rapidly 

Coagulation. 
Strong acid in 
S{ hours 



Declorized flu- 
orescence. Gaa 



Red colonies 
Red, opaque 



Not blackened 
usually 
Yes 



The differentiation of paratyphoid from typhoid bacilli de- 
pends on the second step in bacteriological examination and is 
rendered possible by constant cultural differences in these micro- 
organisms from either the typhoid bacillus or the colon bacillus. 
In the case of stool cultures separate non-acid-forming colonies 
and in the case of blood cultures subcultures on agar from an 
apparently pure growth are subsequently inoculated on the va- 
rious differential media. The most important differential char- 
acteristics are evidenced in the bacteriological chart in Table 
XXIII, which shows the cultural reactions of Bacillus typhosus, 
Bacillus paratyphosus alpha, Bacillus paratyphosus beta, and 
Bacillus coli. The reactions of most diagnostic significance are 
printed in italics, and it is seen that paratyphoid bacilli may be 
differentiated from typhoid bacilli, first of all, by their greater 
fermentative properties in certain of the sugars, glucose, levulose 
and maltose in particular, and that Bacillus paratyphosus beta 
may be differentiated from Bacillus paratyphosus alpha by a 



THE PAKATYPHOIDAL INFECTIONS 207 

characteristic formation of alkali in milk. A more recent method 
of differentiating Bacillus paratyphosus alpha from Bacillus para- 
typhosus beta, and indeed from the typhoid bacillus, rests on a 
characteristic reaction in media containing subacetate of lead, as 
described by Levy and Vallery-Radot. The accuracy both of this 
reaction and of the characteristic formation of a green-colored 
growth on artichoke described by other French authors we have 
been able to verify in our laboratory. Krumwiede, Pratt and 
Kohn find that Bacillus paratyphosus alpha differs consistently 
from Bacillus paratyphosus beta in failing to ferment xylose. The 
most important method of differentiation of paratyphoid from 
typhoid bacilli depends, however, on the agglutination by a 
corresponding specific immune serum. For differential purposes 
of this sort antisera prepared by immunizing rabbits with Bacillus 
typhosus, Bacillus paratyphosus alpha and Bacillus paratyphosus 
beta should be on hand in every laboratory. The titer of such 
antisera should be relatively high, one to ten thousand or twenty 
thousand, and an organism to be classified in any group should 
agglutinate well up toward the titer limit of the serum. All 
examinations of this sort should be carried out by the macroscopic 
method, as already described under the diagnosis of typhoid 
fever. J. Henderson Smith has described an abbreviated method 
leading to the diagnosis, particularly in stools, of paratyphoid and 
typhoid bacilli from Bacillus coli and other bacteria in the follow- 
ing manner: 

The colon group is eliminated by ruling out organisms which 
ferment lactose. 

The proteus group is ruled out by eliminating organisms which 
liquefy gelatin. 

Acid and gas formation on mannite serve to separate paraty- 
phoid and Gaertner organisms from the typhoid group. 

The subsequent differentiation of members of this group would 
depend on the use of an immune serum as described. Bacillus 
paratyphosus beta is separable from Bacillus enteriditis of Gaert- 
ner only by the use of absorbed specific antisera; that is to say, an 
anti-Gaertner serum treated by Bacillus paratyphosus beta will 
still agglutinate the Gaertner bacillus, whereas if the organism in 
question proves to be a Gaertner bacillus, its addition to Gaertner 
immune serum will leave no further agglutinins for the authentic 
Gaertner bacillus. 



208 TYPHOID FEVER 



Diagnosis of Paratyphoid Infections by Means of Agglutination 
Tests 

There is considerable difference of opinion at the present time 
as to the absolute differential diagnostic value of agglutination 
tests in paratyphoid fever. The difficulties in drawing conclu- 
sions from agglutination tests in the case of typhoid fever have 
already been insisted on, and in paratyphoid infections, par- 
ticularly in their differentiation from true typhoid, the difficul- 
ties are still greater. The results are complicated, as in typhoid 
infections, by the possibility of previous vaccination, although 
a positive paratyphoid agglutination test in typhoid vaccinated 
individuals is of more diagnostic significance than a positive ty- 
phoid agglutination test. The second difficulty is brought about 
by the fact that the paratyphoid beta organism is more readily 
agglutinable than either the typhoid bacillus or paratyphoid 
alpha. The main difficulty in differential diagnosis lies in the 
occurrence of group agglutinins. Group agglutinins are more 
likely to be present in a case of true typhoid than in paratyphoid 
infections; that is to say, the serum of a true typhoid case will 
more frequently agglutinate paratyphoid bacilli, as well as the 
causative organism, than under opposite conditions. A certain 
number, probably from eight to ten per cent, of all true typhoid 
cases give positive reactions with one or both of the paratyphoid 
organisms. In the majority of typhoid cases, however, group 
agglutinins for the paratyphoid bacilli are absent. Whenever a 
serum agglutinates the typhoid bacillus best, it may safely be 
assumed that one is not dealing with a paratyphoid infection, 
although the reverse is not true. 

The paratyphoid alpha bacillus is less readily agglutinable 
than the paratyphoid beta bacillus. For that reason positive 
reactions to this organism are of greater diagnostic significance. 
Agglutinins as low as 1 to 40 dilution are of diagnostic significance, 
which is not the case in cases of paratyphoid beta infection. Both 
the typhoid organism and the paratyphoid beta organism may, 
however, be agglutinated by the serum of a case of paratyphoid 
alpha infection, the typoid bacillus more frequently. 

Bacillus paratyphosus beta is, as we have stated, more readily 
agglutinated than the other two organisms under consideration. 
For that reason a positive reaction to be indicative of infection 
with this microorganism should be obtainable in relatively high 
dilutions. Dilutions as high as 1 to 40,000 are not infrequently 
obtained and the percentage of positive results is relatively high 



THE PARATYPHOIDAL INFECTIONS 209 

in true cases produced by this organism. Courmont, Chattot 
and Pierret obtained a positive reaction in eighty-eight per cent 
of their infections due to this microorganism, whereas they ob- 
tained it in only thirty-three per cent of the paratyphoid alpha 
infections, and then in relatively lower dilutions. The serum of 
a paratyphoid beta case less frequently gives group reactions with 
Bacillus typhosus and Bacillus paratyphosus alpha. Inasmuch 
as both typhoid serum and paratyphoid alpha serum agglutinate 
paratyphoid beta to some extent, a negative reaction to this latter 
organism by any given serum is presumptive evidence against 
its being derived from a paratyphoid beta case. 

Doubtless the lack of confidence in differential diagnosis of 
this group of infections by means of the agglutination test is de- 
pendent to some extent on the method employed. We have al- 
ready mentioned under the diagnosis of typhoid fever that the 
macroscopic test should in all instances be used as more accurate 
and as presenting no greater technical difficulty than the less 
accurate microscopic method. Formalinized standard cultures 
of the different organisms are preferable. A method such as the 
one recommended by Dreyer should be employed, the end reac- 
tion determined, and particular note of the rise in agglutinins 
to any particular organisms made on successive examinations. 

Mixed infections may, as we have mentioned, occur and a 
positive agglutination reaction with two or more organisms of 
this group may be due not to the presence of group agglutinins 
but to the occurrence of separate agglutinins for each infecting 
organism. In suspected cases of this sort Castellani's 3 absorp- 
tion method may be employed, although in most hands it has 
not been found as useful for diagnostic purpose with the serum of 
patients as under experimental conditions when a high titered 
immune serum is employed. 



THE INCIDENCE OF THE PARATYPHOID FEVERS 

In statistics referring to the relative prevalence of paratyphoid 
fever as compared with typhoid fever, it is somewhat difficult to 
decide whether data referring to the purely gastro-enteric cases 
of paratyphoid infection have been included or should be included. 
It would be perhaps most useful, particularly in a discussion like 
our own, to rule out all purely gastro-intestinal attacks, inasmuch 
as they may be caused not only by members of the paratyphoid 
beta group of organisms and by the separate Gaertner enteriditis 
group, but by such organisms as Bacillus pyocyaneous, the colon 



210 TYPHOID FEVER 

bacillus and the toxins of Bacillus botulinus. Paratyphoid fever 
has been described in practically all localities of the world, and 
may be considered as widespread as true typhoid fever. Numer- 
ically, however, the paratyphoid infections, even if we include 
the gastro-enteric attacks where paratyphoid bacilli have actually 
been isolated from the stools, are greatly inferior to the true ty- 
phoid cases. In Germany, where most of the statistics have been 
obtained and where the disease is most prominent, Klinger 2 
found that in the southwest in the years 1906 to 1907 there were 
only 307 paratyphoid cases to 3560 true typhoid cases, or some- 
thing like ten per cent. In other statistics from Prussia quoted 
by Uhlenhuth and Hubener, and which were bacteriologically 
proved, there were from the years 1906 to 1909, 1662 paratyphoid 
cases as against 57,955 typhoid cases, only about three per cent. 
In England, Boycott estimates that three per cent of the enteric 
cases are due to paratyphoid bacilli. 

The relation of Bacillus paratyphosus alpha to Bacillus para- 
typhosus beta, in respect to number of infections produced, would 
seem to vary considerably in different countries. In Germany 
statistics show that there are fully ten times as many paratyphoid 
beta cases as paratyphoid alpha cases. Sacqu6p6e and Chevrel 
collected five hundred authentic cases of paratyphosus beta in- 
fections, but only twelve cases of paratyphosus alpha infections 
from the literature. Bainbridge states that paratyphosus alpha 
is, on the other hand, much more frequent in India than the para- 
typhosus beta infections, and this relation has usually been re- 
garded as holding also in the United States. For example, Cham- 
berlain found that the majority of cases on the Mexican border 
in the year 1916 were due to Bacillus paratyphosus alpha, 245 
alpha cases being described to five paratyphoid beta. 

During the present world war numerous systematic studies 
have been made in France as to the relative occurrence of these 
two paratyphoid infections in French troops. It is interesting to 
repeat that the effect of antityphoid vaccination has been to re- 
duce enormously the number of typhoid cases, so that the para- 
typhoid cases markedly predominate, the exact reverse of all 
previous relations, as we have stated. The total number of cases 
of typhoid and paratyphoid fevers has also been markedly re- 
duced, owing to the prevention of the true typhoid infections. 
The relative proportions of paratyphoid alpha and paratyphoid 
beta infections have apparently varied from time to time. Thus, 
Coyon and Rivet, and Grenet and Fortineau 2 found in their 
cases that paratyphoid alpha infections markedly predominated 



THE PARATYPHOIDAL INFECTIONS 211 

in the early part of the war, 124 of the alpha infections being listed 
in their combined reports to thirty-one of the paratyphoid beta 
infections. More recently, however, Labbe 3 and Bernard have 
found an almost reverse proportion of 107 beta cases to thirty- 
nine alpha cases. In a similar manner Archibald, Hadfield, Logan 
and Campbell have noted a sudden change from paratyphoid 
beta fever to paratyphoid alpha in the Dardanelles. The change 
in the relation of these two organisms in Continental Europe 
may to some extent be explained by two facts. In the majority 
of statistics the food poisoning infections have in the past been 
included among the data, and these are due to the beta type of 
infection; and, again, diagnosis based on the agglutination test 
would tend to increase the number of beta infections, owing to 
the greater agglutinability of this organism than of paratyphosus 
alpha. These two facts would indicate that the paratyphosus 
alpha cases may have been more frequent than is indicated by 
the earlier figures we have given. During the war, in addition, 
the source of infection would be a matter of considerable im- 
portance. It is probable that the majority of infections were 
produced by drinking contaminated water, which is more par- 
ticularly a mode of transmission of the alpha type of infection, 
as it is of true typhoid, than of the paratyphosus beta infections. 
Paratyphoid fever resembles typhoid fever in its general dis- 
tribution in reference to season, age and sex. There is not so 
sharp an increase in paratyphoid infections during the summer, 
as is the case with typhoid fever. Both sexes are equally suscep- 
tible, and apparently the greatest incidence in paratyphoid, as 
in typhoid, occurs between fifteen and twenty years of age. 



EPIDEMIOLOGY IN PARATYPHOID INFECTIONS 

Investigations have shown that in general paratyphoid infec- 
tions follow much the same modes of transmission as does true 
typhoid fever, with certain notable exceptions. The order of 
importance in the agents of transmission would seem to be some- 
what different in paratyphoid than in typhoid infections. Food 
stuffs are the most important methods of conveying infection in 
paratyphoid infections, and contact and water follow after them, 
whereas contact and water are the more important modes in the 
transmission of typhoid fever. This greater importance of food 
stuffs is due primarily to the fact that in infections of the para- 
typhoid beta group animals are vitally concerned in the trans- 
mission, which is not the case in typhoid or paratyphoid alpha 



212 TYPHOID FEVER 

fever. We have already referred to the important group of food 
poisoning cases which may be due either to Bacillus enteritidis 
or to Bacillus paratyphosus beta. The importance of these cases 
is suggested by the number collected by Ostertag as occurring in 
Germany from the years 1880 to 1900. He found during this 
period eighty-five epidemics of food poisoning with more than 
4000 cases. There are many more of these infections in Germany 
than elsewhere. Pork, beef and veal are the most frequent sources 
of food poisoning, owing to the characteristic diseases in animals 
which the paratyphoid organisms produce. These diseases are 
transmissible in the meat, particularly when it is not fully cooked, 
and infection of the meat takes place more frequently by intra- 
vital infection of the animals concerned; that is to say, by the 
utilization of the meat of diseased animals and, secondarily, by 
the contamination of butchered meat through handling. Food 
poisoning is rendered possible not only by the fact that the para- 
typhoid bacilli remain living and may multiply in the diseased 
meat unless it is thoroughly cooked, but by the fact that they 
produce toxins which are more resistant than the bacteria them- 
selves. In general, it may be said that the paratyphoid bacilli 
are slightly more resistant to external agents than the true typhoid 
bacillus. 

The transmission of paratyphoid fevers through contaminated 
meat is rendered possible not only by the fact that they are the 
cause of a number of infections in animals, but also by the fact 
that they occur in the intestines of healthy animals, particularly 
in swine, cattle and rats and mice, particularly those that have 
fed on the refuse from slaughter houses. It has also been claimed 
that paratyphoid bacilli may be found in the intestines of healthy 
men, but there seems no reason for supposing that their occurrence 
there in the two to six per cent of cases in which they have been 
reported by some observers, represents any more than the healthy 
carrier condition, which has also been recognized to occur in 
typhoid fever. It is probable that healthy carriers of paratyphoid 
bacilli may be more frequent, owing to the fact that they are 
less likely after ingestion to produce a recognizable infection than 
the true typhoid bacillus. 

PROPHYLAXIS OF PARATYPHOID INFECTIONS 

The prophylaxis of paratyphoid infections rests in the measures 
that are taken against true typhoid infections and in the addi- 
tional precautions as to the thorough cooking of meat and care 



THE PARATYPHOIDAL INFECTIONS 213 

in handling meat after butchering. The precautions that should 
be taken to avoid human carriers of typhoid infections also ob- 
tain in the case of paratyphoid infections. It has been shown 
by Hilgerman, for example, that 3.6 per cent of recovered para- 
typhoid cases remain carriers, and healthy carriers have also 
been described by Prigge and Sachs-Muke. Krumwiede found 
four per cent of healthy carriers in 786 men in the 14th Infantry, 
N. G. N. Y., after its return from Texas. As in the case of typhoid 
infections, the gall bladder remains the main seat of multiplica- 
tion of the bacilli and a focus for further transmission of the 
disease. Paratyphoid bacilli have also been found in gall stones, 
bone abscesses and periostitis, as in the case of typhoid fever. 
Urinary carriers have likewise been described in a few cases. 
Autoinfection of paratyphoid carriers has been shown to be a 
possibility by Prigge and Sachs-Miike. 



CHAPTER XIII 

THE TREATMENT OF TYPHOID FEVER 

This treatise is in no way designed to serve as a clinical manual. 
We are interested, therefore, under the heading of Treatment of 
Typhoid Fever, not so much in discussing the various remedies 
that have been suggested for the alleviation of the symptoms, 
or meeting the complications of the disease. The majority of 
remedies of a medicinal sort have been merely palliative and have 
had little influence in modifying the course of the disease. The 
importance of surgical interference in typhoid fever, particularly 
in relation to its complications, has been fully considered by 
Keen. Our consideration of the treatment of typhoid fever logic- 
ally limits itself to a consideration of certain types of therapy 
which may be regarded as really efficacious in modifying the 
course of the disease or as specific in nature. Although certain 
of the means of therapy we shall consider, as for example hy- 
drotherapy, were first adopted for empirical reasons, all of them 
have sooner or later become related to experimental evidence 
acquired in response to increasing knowledge of the exact mech- 
anism of the disease. 

THE INFLUENCE OF DIET IN TYPHOID FEVER 

R. J. Graves, 1797-1853, is credited by Cole with having been 
the first to introduce liberal feeding in typhoid, and the food he 
advocated was chiefly farinaceous in nature. Other writers since 
that time have in varying degree increased the ordinary feeding 
in this disease, which for the most part has consisted of a milk 
diet. In the last few years much interest and importance has 
attached to the careful experimental studies on diet in typhoid 
by Coleman and his collaborators, which seem based on a thor- 
ough understanding of the pathogenesis and particularly of the 
metabolism during this disease. Coleman and Dubois showed 
that the nitrogen excretion rises and falls with fever, so that in 
typhoid it is increased to forty or fifty per cent beyond the normal. 
They found, however, by comparing the metabolism of starving 
and liberally fed typhoid cases that the increased nitrogen pro- 
duced by feeding was not more than three to five per cent beyond 

214 



TREATMENT OF TYPHOID FEVER 215 

the usual increase which occurred during the fever. They con- 
clude, therefore, that food has little or no dynamic action in 
increasing metabolism. It is important, however, to keep up the 
nitrogen equilibrium, a failure to do which results in the marked 
and often extreme emaciation which accompanies the evolution 
of the disease. 

It was shown by Dubois that proteins, fats and carbohydrates 
are absorbed nearly as well in typhoid fever as under normal 
conditions, but it is found that the nitrogen equilibrium is not 
so well maintained by an increase of fat or of protein as when 
carbohydrates are given in excess (Shafer and Coleman). Cole- 
man, 2, 3 therefore, has recommended and employed a liberal diet 
of milk, cream, butter, eggs and lactose, and finds that a patient 
may actually gain weight during the febrile period provided he 
cooperates and is able to retain nourishment. In a series of 110 
cases Coleman found that the average loss of weight was only 
ten pounds. In a more recent and extensive series totalling 222' 
cases, Coleman 4 claims that the entire picture of the disease is 
changed as compared with control cases. Complications are less 
formidable, the mortality is reduced from fifty to seventy-five 
per cent and the duration decreased. 

It seems possible from the subsequent work of Torrey that a 
carbohydrate diet is of benefit in the treatment of typhoid, not 
only as maintaining the nitrogen equilibrium, but also owing to 
the fact that it tends to modify the intestinal flora. Torrey found 
fewer typhoid bacilli in typhoid cases that were fed on the liberal 
diet and an increased number of acid-producing bacteria (Bacillus 
acidophilus). The suggestion of Collings of the use of Bacillus 
bulgaricus to produce a similar acid medium and thereby inhibit 
the growth of typhoid bacilli, which he regards as having pro- 
duced beneficial effect, is distinctly in line with Torrey's work. 
According to Torrey, Coleman has actually tried the effect of 
cultures of Bacillus acidophilus in a few cases. Alvarez has recom- 
mended the use of acid drinks, particularly of vinegar, possibly 
designed to effect a similar purpose. Liefmann's suggestion of 
sour milk therapy as a means of preventing typhoid carriers has 
already been mentioned. 

HYDROTHERAPY IN TYPHOID FEVER 

Hydrotherapy in typhoid, as in other fevers, comprises not only 
the use of baths and external applications of water, but also the 
drinking of water and other fluids. The use of water in these ways 



216 TYPHOID FEVER 

has been alternately encouraged and discouraged in the evolution 
of medical practice. We are told by Cayley (Murchison) that 
Antonius Musa, a Roman physician, became famous through his 
treatment of the Emperor Augustus by cold baths when he fell 
ill of typhoid, and at all events the method must have been prac- 
ticed in remote antiquity. It was, however, towards the end of the 
eighteenth century (1797) that Currie f rst described the benefits 
which followed the liberal application of cold water in typhoid and 
typhus fevers. He used for the most part cold sea water, which was 
poured over the patient, who had been seated for the purpose in a 
chair. Currie's method gained no considerable vogue until it was 
revived by Brand in 1861, since which time it has been freely 
advocated by the majority of physicians who have tried it. There 
would seem to be a unanimous conclusion in the use of hydro- 
therapy that at least it is harmless in all conditions of typhoid, 
except in perforation and hemorrhage, and that it apparently does 
considerable good. There is distinct evidence that the mortality 
is lowered, although the evidence is not so definite that the duration 
of the disease is lessened. 

External hydrotherapy in typhoid is practiced in one of three 
ways: by cold sponges, the cold pack, or by the bath, the latter 
being the more usual method and the one advocated by Brand. 
Baths are given usually with water at a temperature of from 65° 
to 70° Fahrenheit for about fifteen minutes, either when the tem- 
perature has risen to 102° or more, or as a routine, irrespective of 
the height of the temperature, during the febrile period every three 
hours. The exact temperature of the bath has varied in the hands 
of different physicians, some preferring to give a tepid bath or 
bath with a temperature above 70° Fahrenheit, particularly for 
the first few times. The method should vary a good deal in accord- 
ance with its acceptance by the patient. 

Apart from its apparent effect in reducing the mortality some- 
what in any considerable series of cases, the cold bath acts oy 
reducing the temperature temporarily for a degree or more, which 
would seem of advantage. It allays the nervous symptoms, in- 
creases diuresis and diminishes arterial tension. Although the 
reduction in the temperature is transitory and not very marked, 
it would appear to be of temporary benefit to the patient, who 
usually feels better following its administration. There are two 
essential symptoms following the bath which we suggest may be 
of significance in explaining its beneficial effect, an effect which 
is more marked in other methods of specific therapy which exag- 
gerate these symptoms and through them apparently lead to more 



TREATMENT OF TYPHOID FEVER 217 

striking results. It is agreed by all observers that the bath to be 
effective should produce a distinct chill in the individual, and this 
chill, moreover, is accompanied by a hyperleucocytosis (Thayer). 

TREATMENT OF TYPHOID FEVER BY MEANS OF SERA 

The possibility of an effective serum therapy in typhoid fever 
has been long and seriously considered by many investigators, 
but we find it extremely difficult to pass any judgment, not only 
on the results that have been obtained, but even on the value of 
the evidence that has led to the advocacy of the various types of 
serum employed. 

Certain aspects of serum treatment may easily be disposed of 
before proceeding to a discussion of the more extensive work on 
the use of various types of immune serum obtained from animals. 
In two lines of investigation at least the serum of individuals who 
have recovered or are successfully resisting typhoid infection have 
been employed in treating the disease. Von Jaksch and Walger 
were apparently the first to employ the serum of recovered cases 
of typhoid fever in treatment, and the results they obtained were 
at least encouraging. This type of treatment has recently been 
revived by Petrovitch, who was apparently able to reduce the 
mortality in nearly 500 cases of typhoid by treating them with the 
serum either of convalescents or of immunized individuals; whereas 
the mortality in the 487 treated cases was 4.3 per cent, in 1020 
controls during the same period it ran as high as 12.8 per cent. 

Autoserumtherapy has been recently suggested by Koenigsfeld, 2 
and by Ramond and Goubert. Koenigsfeld withdraws the blood 
from a given case of typhoid in considerable amount and subse- 
quently inoculates the individual subcutaneously with his own 
serum daily in doses of from two and one-half to four cubic cen- 
timeters. In fourteen of the eighteen cases treated in this manner 
the individuals would seem to have been bettered, and particularly 
those cases that showed a high Widal at the time at which the 
serum was withdrawn. Ramond and Goubert have treated fifty 
cases by withdrawing the blood from the vein and immediately 
injecting it subcutaneously in a neighboring locality. Good results 
would seem to have followed this method in some thirty-eight per 
cent of their cases, whereas no effect is claimed in forty-four per cent. 

Numerous specific immune sera derived from horses, goats and 
other animals have been employed in the treatment of typhoid 
fever. Extraordinarily good results have been claimed by a few 
observers, although the benefit produced by this method of treat- 



218 TYPHOID FEVER 

ment has in the hands of the majority remained merely encour- 
aging. The immune sera employed have varied considerably in 
their method of preparation, which has depended on the individual 
conception of the investigators as to the nature of the harmful 
results produced by typhoid infection, the type of antibodies that 
may most logically be used in combatting them, and, finally, the 
most successful manner of producing these desired antagonistic 
substances. We have already discussed the question of the nature 
of the poisons present in or excreted by the typhoid bacillus, than 
which no subject is more involved in a mass of experimental data, 
and concerning which little ultimate opinion may at the present 
time be offered. As we have already stated, it has been known 
since the time of Brieger and his collaborators that cultures of the 
typhoid bacillus are toxic for experimental animals, although in the 
oiiginal experiments the possible toxicity of culture media still 
further complicated the findings. The work of Bandi, Chante- 
messe, 2 Rodet, Aronson, Meyer and Bergell, Kraus and Stenitzer, 
and Yamanouchi would indicate that true soluble toxins are pro- 
duced by the typhoid baccillus under favorable conditions of 
temperature and culture medium, although these toxins in no 
wise approach in strength and importance the true exo-toxins, 
such as those produced by tetanus and diphtheria bacilli. On the 
other hand, beginning with the work of Pfeiffer and Kolle, 2 1896, 
a growing series of observations by Martin, McFadyean and 
Roland, Sanarelli, Conradi, 6 Balthazard, Besredka and others 
would attribute a major importance to the endo-toxins derived 
from the bodies of the bacilli rather than to any products formed 
in their growth. We have already stated our opinion that no sharp 
differentiation in the essential nature or properties can be drawn 
between the endo- and exo-toxins. It would appear that the occur- 
rence of the soluble toxin would depend simply on the strain 
of bacteria used, and the ease with which the toxin is eliminated, 
which in turn depends largely on the culture medium employed. 
This point of view is rendered probable by the work of Arima 2 
and others, which shows that antibodies directed against either 
the soluble or the endo-toxin, respectively, neutralizes both poisons. 
The majority of antisera employed in the experimental studies of 
typhoid infection and in the treatment of typhoid fever have been 
prepared with the design that they should be antitoxic rather than 
anti-infectious, in order to produce the desired result. In other 
words, they have been designed to neutralize the poisons in the 
typhoid bacillus rather than to promote directly or indirectly 
the destruction of the bacteria themselves. It is by no means cer- 



TREATMENT OF TYPHOID FEVER 219 

tain which result should be aimed at in the combatting of typhoid 
infection, and it is indeed probable that both results have to some 
extent been realized by many of the sera prepared, independent of 
the guiding thought that has led to their preparation. It is prob- 
able that an immune serum formed in response to the injections of 
living or dead bacteria will differ only in degree from an immune 
serum produced in response to the injections of extracts of such 
bacteria, and, indeed, the most successful typhoid antisera which 
we are about to describe have been produced by injections of both 
preparations. It may promote exposition to discuss certain of the 
best-known typhoid antisera without further attempt to outline 
the principles involved in their manufacture. 

Antiserum of Chantemesse 

Shortly after his description of a soluble toxin from the typhoid 
bacillus Chantemesse 2 prepared an antiserum by immunizing 
horses with this preparation for a long period of time. The vir- 
ulence of the microorganism was supposedly increased by its 
growth on a medium containing spleen extract. This serum was 
subsequently studied in detail by Balthazard, a pupil of Chante- 
messe, who, however, arrived at the conclusion that the toxins 
of the bacillus were largely intracellular in nature. Balthazard 
finds that Chantemesse's serum agglutinates the typhoid bacillus 
in very high dilution and protects experimental animals, owing 
to its power of destroying the living organisms and of protecting 
the leucocytes from the endotoxins. Chantemesse has claimed 
extraordinary success following the use of this serum. He injects 
very small amounts, in fact only a few drops, subcutaneously, 
and one injection is usually all that is necessary. No claim is 
made that the disease is remarkably shortened, although the tem- 
perature usually falls a degree or so within a few days after in- 
jection. In 1000 cases, however, the mortality was reduced to 
4.3 per cent, whereas in Paris hospitals during the same period 
seventeen per cent of the untreated cases died. It seems sur- 
prising that this serum has not been more generally employed 
if its results are really as significant as they appear to the author. 
Josias seems also to have had favorable results with the serum, 
and no negative evidence to disprove its value has appeared. 

Besredka's Antiserum 

Besredka 4 prepared an antiserum by immunizing horses against 
endotoxins which he derives from the typhoid bacillus by drying 
the cultures, grinding them with salt and then extracting the 



220 TYPHOID FEVER 

poisons. Very little practical results have been reported from 
the use of this serum, although it has been tested experimentally 
by Pfeiffer and Bessau, 2 Arima 2 and others. Pfeiffer and Bessau 
claim to have demonstrated that Besredka's serum is not pri- 
marily anti-endotoxic as originally claimed, but does destroy the 
organisms when injected simultaneously with them in animals. 
Arima 2 found that Besredka's antiserum would neutralize both 
the exo- and endotoxins which he has described and differentiated. 
Andriescu and Ciuca found that on administering this serum in- 
travenously in human cases the microorganisms disappeared rapidly 
from the circulating blood. Montefusco apparently obtained some 
benefit in a few serious cases with Besredka's preparation. 

An anti-endotoxic serum from goats has also been used by 
Ludke 2 with good results in a few cases of typhoid. The anti- 
toxin produced by Kraus and Stenitzer by immunizing animals 
with their soluble toxins has apparently been used to some ad- 
vantage in sixteen cases by Gaupp, who administered the serum 
intravenously. Serum has been prepared also by immunizing 
animals with sensitized cultures of the typhoid bacillus by Garbat 
and Meyer and by Karaffa-Korboutt. Garbat and Meyer give 
good experimental evidence which led them to anticipate better 
results from a mixture of sera of animals that had been immunized 
on the one hand with sensitized bacteria and on the other with 
untreated typhoid bacilli. Their contentions, however, did not 
seem to be borne out in practice by Rommel and Hermann. 
Perhaps the most encouraging results that have been obtained 
by serum therapy in typhoid have been in the hands of a number 
of French observers, who have employed a serum prepared by 
Rodet, 2 who immunized horses intravenously both with living 
bouillon cultures and with old endotoxins from the typhoid bacillus. 
The results of treatment with this serum have been reported 
on favorably by Rodet and Lagriffoul, Remond-and Minvielle, 
by Etienne and by Rodet himself. Rodet 3 summarizes the re- 
sults in 400 cases and finds that repeated injections of this serum 
in doses of from ten to twenty cubic centimeters given subcu- 
taneously every other day result in markedly decreasing the dura- 
tion of fever in cases that are treated early in their course, and 
may lead to an abortive cure in six or eight days in the most fa- 
vorable of them. Etienne obtained similar results in some 200 
cases. In short, this serum would seem the most favorable one 
hitherto described, and its mode of action suggests certain anal- 
ogies to, although less striking results than those obtained by 
the use of vaccines, to a consideration of which we may now turn. 



TREATMENT OF TYPHOID FEVER 221 



VACCINE TREATMENT IN TYPHOID 

In 1893, Eugene Fraenkel began treating cases of typhoid 
fever by subcutaneous injection of killed cultures of Bacillus 
typhosus, and obtained results which to his mind were encourag- 
ing. Little interest was at first awakened by Fraenkel's work, 
except in relation to the specificity of the treatment by Rumpf 
and others, to which reference will subsequently be made. In 
1902, Petruschy 2 used a combination of vaccine and immune 
serum in typhoid, and in 1908 Pescarolo and Quadrone advocated 
the use of living avirulent cultures. Following the interest in 
vaccine therapy awakened by Wright, increasingly frequent re- 
ports on the possible value of typhoid vaccines in typhoid fever 
have appeared. In 1912, Callison summarized the results ob- 
tained by numerous authors, chiefly English and American, in 
747 cases, and in 1915, Krumbhaar and Richardson could collect 
over 1800 cases reported on by forty authors. The original 
method prescribed by Fraenkel, the subcutaneous injection of 
killed typhoid cultures, is apparently being used with increasing 
frequency by physicians. The best studied groups of cases treated 
in this manner, however, give ground for little unrestrained en- 
thusiasm as to results produced, and certainly no claim is made 
that anything approaching a specific type of therapy has been 
obtained by this method. The majority of physicians would 
seem to be following blindly certain general ideas of vaccine 
therapy that have tardily permeated the clinical world through 
the work of Wright. The best that may be said is that Fraenkel's 
vaccine therapy in typhoid may cause a shortening of the course 
of the disease, a lower mortality, and probably also fewer relapses 
and complications. The demonstration of these beneficial effects 
is, however, difficult in any particular series of cases, owing to 
the necessity of the employment of statistical methods which 
include as a prerequisite large numbers of cases and adequate 
controls, such as are rarely or never obtained in the experience 
of any one investigator. We shall attempt an analysis of the 
results of recent workers who have employed this method, after 
having described certain radical modifications in it which we 
believe have led to a far more specific type of therapy. 

In the last four years two modifications have been made in the 
use of vaccines in typhoid, which have furnished results in a large 
and growing group of cases that may be regarded as strongly 
indicative that a specific type of therapy is being arrived at in 
this disease. We use the expression "specific" here in its largest 



222 TYPHOID FEVER 

sense of "definite," and not in the narrower bacteriological and 
immunological sense which correlates some definite result with 
the specific etiological agent in the disesae. The results which 
we shall describe are, at least in part, due to a non-specific pro- 
tein reaction, which may be produced at least to some degree by 
the employment of a number of proteins which have no relation 
to the typhoid bacillus. The two innovations in Fraenkel's 
method, to which we have referred, are, first, the injection of the 
vaccine intravenously, and, secondly, the use of sensitized in 
place of ordinary untreated vaccine. The first of these innova- 
tions would seem more important than the second, although 
there is very distinct evidence that sensitized vaccines work 
better than unsensitized, as we have judged to be the case in 
prophylactic immunization against the disease. 

The intravenous injection of typhoid vaccines in typhoid fever 
was first mentioned by Thirloix and Bardon in 1913, who showed 
that two to ten million bacteria could be injected in this manner 
without harm and with much better result than when larger 
doses were given subcutaneously. This method was further 
amplified by Ichikawa in the following year, who gave intravenous 
injections of typhoid bacilli that had been treated and thereby 
sensitized with the serum of convalescent cases. In addition to 
a large number of authors who have reported on results obtained 
by each of these methods, we find an intermediate group who 
have used sensitized vaccines subcutaneously. We have made a 
careful and fairly comprehensive analysis of the various reports 
made in the last five or six years on the use of each of the types of 
vaccine therapy to which we have briefly referred, and present them 
as of suggestive value. 

TABLE XXIV * 

SUMMARY OF RESULTS OBTAINED BY RECENT OBSERVERS (1913-1917) IN THE 
TREATMENT OF TYPHOID FEVER BY VACCINES ADMINISTERED IN VARIOUS 
WAYS 

Observers Total Estimates Benefitted Mortality 
Cases based on 
Untreated vaccine 

subcutaneously 30 1001 

Sensitized vaccine 

subcutaneously 14 593 

Untreated vaccine 

intravenously 22 501 

Sensitized vaccine 

intravenously 12 487 

* The authors referred to in this summary are herewith given, a division 
being made in respect to the type of vaccine employed and its method of ad- 



512 


46% 


14.5% 


239 


69% 


8.0% 


233 


62% 


13.0% 


316 


85% 


11.0% 



TREATMENT OF TYPHOID FEVER 223 

A careful study of this table will bring out a number of facts 
which a mere cataloguing of the results obtained by each of the 
authors quoted could not convey. It will be noted, first, that the 
most frequent method of vaccine therapy not only has been but 
continues to be the subcutaneous injection of ordinary and, usually, 
of heat-killed typhoid bacilli. The results by thirty authors are 
quoted as contrasted with twenty-two that have used similar 
vaccines intravenously, and a still smaller number that have used 
sensitized vaccines either subcutaneously or intravenously. The 
total number of cases gathered from these various reports would 
likewise show a predominance of subcutaneous plain vaccine 
treatments. The reports cited vary markedly in their complete- 
ness, many of the writers failing even to give the number of cases 
they have treated, and others making only the most general re- 
port on the results obtained. In the third column are found the 
total number of cases in each group on which a definite statement 
has been made as to the number benefitted. The grounds on 
which a claim of benefit is made are again found to vary markedly, 
and will be more fully discussed when we come to consider the 
actual effect of the vaccine injections in each of the types of 
therapy referred to. The percentage figures, then, under the 
heading of benefitted must be admitted to be distinctly affected 
by subjective influences. We believe, however, that they are of 
more than suggestive value. The mortality figures would not 
seem to vary strikingly between the groups listed, and to be all 
within the normal limits of untreated cases, although they cer- 

ministration, as in the table. (1) Recent authors reporting on the use of un- 
treated vaccine subcutaneously: 1911, Fletcher; 1912, Sadler, Callison; 1913, 
Fornet; * 1914, Josue and Belloir, Weil, Sacquep6e and Chevrel, 2 Guinon and 
Malarte, Pensuti; 1915, Goldscheider and Aust, Bourke, Evans and Rowland, 
Feistmantel, Mertz, Peiper, Krumbhaar and Richardson, Groer, Wiltshire 
and MacGillycuddy, Reiter, LOvy, Lucksch and Wilhelm, Peutz; 1916, Whit- 
tington, Zupnik, Miiller and Leiner, Waitzfelder. (2) Authors who have em- 
ployed sensitized vaccine subcutaneously: 1912, Ardin-Delteil, Negre and 
Raynaud; 2 1913, Ardin-Delteil, Negre and Raynaud, Roques, Boinet; 1915, 
Petrovitch, Garbat, 3 Feistmantel, Szecsy, Liebermann, Fellner, LQwy, Lucksch 
and Wilhelm, Boral, Deutsch; 1916, Galambos, G. Mayer. (3) Authors who 
have injected untreated vaccine intravenously: 1913, Thiroloix and Bardon; 
1914, Kraus and Mazza, Kraus; 1915, Biedl, '■ 3 Ditthorn and Schultz, Csernel 
and Marton, 1 . 2 Reibmayr, Mazza, McWilliams, Holler, Paulicek, F. Meyer,* 
Rhein, Lentz, Ortiz, Acuna and Belloc; 1916, Faginoli, Petzetakis, Zupnik, 
Miiller and Leiner, LO.vy, Lucksch and Wilhelm. (4) Authors who have in- 
jected sensitized vaccine intravenously: 1912, Ichikawa; 1914, Meyer and 
Altstaedt; 1915, Biedl, 1 - 2 Eggerth, Holler, 1 - 2 Sladek and Kotlowski, Koranyi, 
Landsberger, LOwy, Lucksch and Wilhelm; 1916, Rohonyi, Galambos; 1917, 
Caronia. 



224 TYPHOID FEVER 

tainly possess an objective value. We believe that the striking 
difference in percentage which emerges from the statistical study 
of these authors and cases that we have mentioned, as between 
those cases treated subcutaneously by ordinary vaccines and 
those treated intravenously by sensitized • vaccines, a difference 
of nearly one hundred per cent, represents a conservative rather 
than an exaggerated statement of the importance that has been 
made in recent modifications in vaccine therapy in typhoid. A 
discussion of the actual type of benefit produced, or rather of the 
results which follow in the actual treatment of cases, should now 
be more fully presented. 

The results of our personal experience in the intravenous vac- 
cine therapy of typhoid fever have not been included in the sum- 
mary presented in the last table, as it seems advantageous to 
use them as a separate basis of discussion of the results produced 
by this method of treatment. Our own results vary only in de- 
gree from those obtained by the authors we have cited. We 
were led independently and before the publications of Thiroloix 
and Bardon and Ichikawa to suggest and later to employ intra- 
venous vaccine therapy for the following reasons (Gay 2 ). Cer- 
tain of the experimental studies of Gay and Claypole 4 in the 
typhoid carrier condition in rabbits brought out the interesting 
fact that the injection of typhoid bacilli in immunized rabbits 
gave rise to a grade of leucocytosis which was to some extent 
specific. The injection of any foreign protein in an animal pro- 
duces a transitory leucopenia followed by an increase in the 
polymorphonuclear leucocytes, and the typhoid bacillus or its 
extractives produces such a result in normal rabbits. When, 
however, the same number of typhoid bacilli are injected in a 
rabbit that has been previously immunized against this micro- 
organism, the degree of leucocytic increase is considerably in- 
creased over what occurs in the normal animal. This increased 
leucocytosis would seem to be due to the presence of immune 
bodies in the serum of such immunized animals, which act as 
tropins and render the injected bacteria more attractive for the 
leucocytes. This would seem to be proved by the fact which 
Gay and Claypole demonstrated, not only with typhoid bacilli 
but with red blood cells, that a sensitized antigen will give rise 
to a higher grade of leucocytosis in normal animals than an un- 
treated antigenic substance. In the case of carrier rabbits it was 
possible to demonstrate that the production of this specific type 
of hyperleucocytosis is coincident with the diminution or dis- 
appearance of bacteria in the body of the carrier, and it was 



TREATMENT OF TYPHOID FEVER 225 

therefore suggested that a similar stimulation of leucocytes might 
be of advantage in treating cases of typhoid fever which are char- 
acterized by the diminution in polymorphonuclear leucocytes. 
It was judged that the type of sensitized vaccine sediment which 
we had advocated in prophylatic vaccination against typhoid 
would be most serviceable for therapeutic uses of this sort, not 
only as stimulating a greater leucocytic response, but as being 
less toxic than the untreated vaccines. The superiority of sensi- 
tized over unsensitized vaccines in treatment would appear evi- 
dent from the summary of the literature which we have already 
offered. In addition to the agreement as to the higher percent- 
age of benefit obtained by these vaccines, may be mentioned ob- 
servations of certain authors who have used both sensitized and 
unsensitized vaccine in treatment and report better results with 
the first than with the second preparation. Such conclusions 
were drawn by Paltauf, Holler, and Feistmantel on the basis of 
comparative experience with the two vaccines. Our results 
(Gay, 2 Gay and Chickering, Gay 3 ) with the use of sensitized 
vaccine sediment, although not compared with the use of other 
vaccines, would seem as successful as any that have been re- 
ported. 

The intravenous injection of sensitized vaccine sediment pro- 
duces a series of distinct symptoms which vary markedly in in- 
tensity with individuals and with the dose employed. The usual 
amount on initial injection has been one-fiftieth of a milligram 
(corresponding to 150 million bacteria), and a corresponding 
dose in children, who, as in prophylactic immunization against 
typhoid, react less markedly than adults to corresponding amounts. 
We shall later refer to the findings of other investigators who 
have used other vaccines intravenously and who have described 
alarming or even dangerous symptoms following their employ- 
ment. It should be noted, however, that our vaccine, owing to 
its sensitization and the removal of endotoxins, certainly gives 
less perturbing, and, so far as we have observed, no really untoward 
effect. It seems necessary to produce a moderate reaction in 
order to effect the desired result, and the dosage in successive 
inoculations has been increased slightly in order to produce a 
similar train of symptoms on each inoculation, which a continu- 
ance of the same dose usually fails to do. The injection of the 
vaccine intravenously is followed in from fifteen minutes to an 
hour by a chill, which lasts for a few minutes to ten or fifteen. 
This chill, or shaking, is not accompanied by a feeling of cold- 
ness, but rather by a sense of involuntary, spasmodic, muscular 



226 TYPHOID FEVER 

contraction. The chill is accompanied by a rise in temperature 
of one to three degrees, which reaches its height within three 
hours after injection and then falls. There may be a rise in tem- 
perature without a chill, or the reverse. The rise in temperature 
is accompanied by a leucopenia, which may fall as low as 2000 to 
3000 to the cubic centimeter. The chill is accompanied by an 
increase in the pulse rate and may be accompanied by slight 
cyanosis, slight respiratory distress, and frequently a sense of 
discomfort. According to Scully, the blood pressure rises during 
the chill and then falls. 

The temperature reaches normal or sub-normal in about twelve 
hours. This fall in temperature is accompanied by sweating, 
which may be profuse and last for several hours, relaxation, and 
usually general amelioration of such symptoms as headache, 
delirium and the like. The patient often feels perfectly well, 
and this condition, even when transitory, seems beneficial. Co- 
incident with the fall in temperature there occurs a rise in the 
leucocytes, which may reach as high as 40,000 and which are 
characterized by a relative polymorphonuclear increase. We 
shall later refer, in reviewing the work of others with similar 
methods, to the dangers that have appeared with slightly different 
vaccine preparations, and to the contra-indications to such in- 
jections that undoubtedly exist. We may repeat, however, that 
in our experience of 1200 injections reactions of this sort have 
never appeared harmful, either immediately or ultimately, and 
contra-indications seem, in the light of increasing experience, to 
grow progressively fewer. 

No detailed method of procedure can be prescribed for treat- 
ing any given case of typhoid fever by this method. The best 
results seem to be obtained by provoking a distinct but not too 
severe reaction of the type outlined. The dose necessary to pro- 
duce such a result varies markedly with the individual and the 
particular balance already established between the typhoid 
bacillus and the reaction antibodies in the host. The temporary 
drop of temperature to normal may become permanent and re- 
main there, in which case no further injections are required, ex- 
cept for the prevention of relapse. If the temperature again 
rises over a period of two or three days, the injection should be 
repeated in slightly increased amount, and so on until the desired 
result is produced or further injections are judged futile. A con- 
siderable number of injections may be given with perfect safety. 
As many as fifteen or sixteen have been given in certain instances, 
but if no striking result is obtained following three or four injec- 



TREATMENT OF TYPHOID FEVER 227 

tions at two or three day intervals, very little effect from further 
treatment may be expected. 

It has seemed wise to us previously to separate our cases into 
three rather definite groups in respect to the results produced by 
the vaccine injections. We believe that this grouping, based on 
results produced, is a conservative one and by no means represents 
all the benefit that attends this method of treating typhoid fever. 
We have briefly referred to the fact that the temperature excursion 
with return to normal is accompanied by subjective feelings of 
well being, although at times of slight weakness, and would seem 
to be both immediately and ultimately of benefit to the patient. 
Such subjective amelioration is, of course, open to error in inter- 
pretation, but would seem, not only to us but to others who have 
watched our cases, to be frequent and of a convincing nature. 
The nurses, for example, in charge of the cases not only volunteer 
remarks as to the benefit produced by the vaccine injections, but 
emphasize the lessened care which patients treated in this manner 
entail. We prefer, however, to base our judgment as to the good 
results of the method rather on the more objective results that 
have been produced, the shortening of the duration of the fever, 
its frequent abrupt termination in an abortive form, the lessening 
of mortality and of complications in particular. We have classified 
the three groups of results obtained as abortively recovered, as 
benefitted, or as unaffected. Cases illustrative of each of these 
types of result produced by the vaccine injection are given in the 
reproduced clinical charts in Figures 4, 5, and 6, which are ex- 
plained in their footnotes. 

A summary of our ninety-eight cases classified under these three 
headings proves of interest not only in respect to results achieved, 
but as bearing on the mechanism by which it is effected. In 
Table XXV are expressed certain characteristic findings in each 
of these groups of cases under consideration, which we may briefly 
refer to in drawing certain conclusions as to their significance. 

TABLE XXV 

SUMMARY OP RESULTS IN 98 CASES OP TYPHOID TREATED BY INTRAVENOUS 
INJECTION OP SENSITIZED VACCINE SEDIMENT 

No. Widal Titer Blood Treatment No. of p„ mnnpn , Days 

of Age. on beginning Culture. begun. treat- Znrrnnl °f 

Cases. treatment. Positive Day. ments. " ormai - treatment 



Aborted 


33 


26.2 


296.0 


36.6% 


13.4 


1.88 


20.4 


7.0 


Benefitted 


32 


24.2 


156.5 


70.9 


14.8 


3.20 


30.6 


15. S 


Unaffected 


33 


28.8 


114.8 


84.8 


13.7 


4.85 


46.8 


33.1 



TYPHOID FEVER 



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ILLNESS. 


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16 


17 


18 


19 


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ILLNESS 




















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Fig. 4. — Temperature chart in an abortively cured case of typhoid. The 
temperatures recorded are rectal and give the forenoon and afternoon maximum 
of each day. The mark X represents the time at which vaccine injections were 
given intravenously and the number of million bacteria (200 M) in that par- 
ticular dose. Above are indicated the results from blood cultures (B. C.) and 
the strength of the Widal test (W+l-80). Any temperature at or below 100° 
by the rectum is regarded as normal. 



TREATMENT OF TYPHOID FEVER 



229 



In the first place, it will be seen that our cases may be divided 
into three almost exactly equal groups in respect to results pro- 
duced. These groups, moreover, are of almost identical age, and 
it is also found that treatment was begun on the average at prac- 
tically the same time in the three groups. They differ in prac- 
tically all other respects. We find, in the first place, that anti- 
body formation, as evidenced by the Widal or agglutinin titer in 
the cases before injections were begun, varies markedly in accord- 



OAT 

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ILLNESS 


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Fig. 5. — Temperature chart in a benefited case of typhoid fever treated 
by intravenous vaccine injections. Notations as in Chart 4. 

ance with the eventual outcome of the case in question. In the 
abortively cured cases the Widal is found to be on the average over 
twice as high as in the unaffected cases, whereas the benefitted 
cases lie intermediate between the two groups. A strong Widal 
is evidence, then, of a good prognosis, not only in respect to these 
treated cases but probably also in untreated cases, to judge from 
the experience of others. Inversely correlative with the strength 
of the Widal is the occurrence of the percentage of positive blood 
cultures in the three categories under discussion; whereas the cases 



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Fig. 6. — Temperature chart in a case of typhoid unaffected by intravenous 
vaccine injections. Notations as in Chart 4. A. T. refers to an antityphoid 
serum also givenintravenously. 



TREATMENT OF TYPHOID FEVER 231 

that respond less well to treatment are found to give positive blood 
cultures in nearly eighty-five per cent of cases, those that recover 
abruptly on treatment had positive blood cultures in only 36.6 
per cent. The benefited cases, again, He intermediate between 
the two. These relations between blood cultures and antibody 
formation we have already referred to as representing a balance 
established in the patient before intervention between the in- 
fecting agent and the resisting power of the host. When the re- 
sisting power is strongly developed, a favorable outcome may be 
more confidently expected. 

The group of cases which we have classified as abortively cured 
or abortively recovered suggest in some respects the mild or abor- 
tive typhoid cases which are discussed in most extensive mon- 
ographs on this disease. The typhus levissimus of Griesinger, the 
typhoidette of Brouardel, or abortive typhoid forms a well 
recognized group or groups that must occur in every considerable 
collection of cases of typhoid fever. Estimates vary as to the exact 
proportion of such cases, as may normally be expected. It is 
probable, as Curschmann suggests, that at least two groups should 
be formed, the mild typhoid fevers and the abortive typhoid fevers, 
the latter more frequently though by no means invariably char- 
acterized by a somewhat abrupt rise and fall of temperature and 
an abbreviated fastigium. McCrae in his 1500 cases found three 
per cent of mild forms of the disease, and, in addition, 0.1 of one 
per cent of his cases recovered by crisis. Letulle found that these 
two types of the disease occurred particularly in certain epidemics 
and in children. He finds something over seventeen per cent in 
the cases of the disease which he collected. This figure may cer- 
tainly be regarded as an extreme maximum of occurrence. Accord- 
ing to Curschmann, the abortive and mild forms frequently have 
only three to six days of fever and almost never over ten or twelve 
days, with which statement Hare and Beardsley would agree. 
At all events, the cases of mild and abortive typhoid together must 
constitute a relatively small percentage of all, in spite of the figures 
of Letulle. Hare and Beardsley note that Coleman found only 
twenty-four such cases in five years' experience at the Bellevue 
Hospital in New York. At all events, no such number as one-third 
of all the cases, as in our series, could be found in this way without 
some type of intervention. It may further be noted that our cases 
almost invariably have occurred beyond the limit of ten to twelve 
days set by Curschmann, and have practically invariably been 
characterized by a critical fall of temperature, and what is more 
important still, show a direct relation between this critical fall and 



232 TYPHOID FEVER 

the injection of vaccine. Our cases do not represent the mild 
epidemics of Letulle, nor has any considerable number of them 
been furnished by children. They have been gathered over three 
seasons and in widely different localities. As may be anticipated, 
the abortively recovered cases represent by and large, when es- 
timated before treatment was begun, the milder cases of the dis- 
ease in this series. Our characterization of a preponderance of 
these abortively cured cases as milder has no relation, however, 
to the small group of mild and abortive forms that have just been 
discussed. We have endeavored to register our impression as to 
the severity of each case before treatment was begun, and our 
results are expressed in Table XXVI, where it is found that many 
more severe cases occur among those that remain unaffected by 
treatment, and many more mild cases occur among those that 
are aborted, whereas the benefitted cases would seem to lie inter- 
mediate between the two. 

TABLE XXVI 

GENERAL CONDITION OF CASES BEFORE TREATMENT 





Severe 


Moderate 


Mild 


Unaffected 


26 


6 


1 


Benefitted 


10 


17 


5 


Aborted 


4 


13 


16 



It is evident, then, that the milder cases react better to treat- 
ment than the more severe, but even the most severe ones will in 
some instances at least be benefited and even aborted. We be- 
lieve the effects actually produced are best represented by the 
figures given under "Permanent normal temperature" and "Dura- 
tion of treatment" in Table XXV. It is found that a permanent 
normal temperature was obtained in the third of the cases that are 
called aborted on an average at about the twentieth day. When 
we consider that the treatment of these cases was not begun until 
the thirteenth day, the really significant figure of seven days as 
the average duration of treatment required to restore the patient 
to an essentially normal condition, so far as the temperature is 
concerned, is obtained. We find, moreover, that it took on the 
average a little under two injections to produce this result. The 
fall of temperature by crisis, which is exemplified in the figure 
(Figure 4) used to illustrate the abortive cure, is characteristic of 
this category, although the abrupt fall may not occur in every 
instance on the first injection. 

The benefited cases, again, are well typified in the illustrative 



TREATMENT OF TYPHOID FEVER 233 

chart (Figure 5); each successive injection of vaccine produces a 
permanent fall in temperature on the average of one degree, and 
it may require several, on the average a little over three injections, 
to reduce the temperature to a permanent normal. The average 
duration, then, of these cases is found to be 30.6 days, and the 
duration of treatment the more significant figure, 15.8 days. 

The cases that have been listed as unaffected, although showing 
the ordinary temperature excursions following each injection, are 
characterized by a prompt return of the temperature to its original 
or nearly its original height. The impression has remained in the 
minds of many who have seen those cases that they are really 
benefited, but since we have taken the reduction of temperature 
as our criterion of results, we prefer not to emphasize any good 
effect that may have occurred in these cases, beyond the diminu- 
tion in complications and mortality, to which we shall presently 
refer. Even in this group of cases the average duration is by no 
means extraordinary, 46.8 days, although it does exceed somewhat, 
perhaps, a normal average duration of cases of typhoid fever. It is 
extremely difficult to estimate what such an average duration 
usually is. Curschmann regards the mild cases as lasting on an 
average of twenty-one to thirty-three days. In McCrae's 7 figures 
the average febrile period was thirty-one days. It should be noted 
that our figures refer to the total duration of the disease from its 
initial symptoms, so far as they can be estimated from the patient's 
history, and not from the known duration of the fever itself. The 
group of cases, then, that were best affected may reasonably be 
regarded as having run a distinctly short course, and the average 
of all cases, which is about twenty-nine days, is not markedly 
different from McCrae's thirty-one days. 

The mortality in this series of ninety-eight treated cases is 6.6 
per cent, which, when we consider that the cases were treated 
over a period of three seasons under varying conditions of care 
in private houses as well as hospitals, and, moreover, treated in 
different parts of the country, is certainly a very satisfactory 
figure. The average mortality is usually figured at ten per cent. 
The cases of death were predominantly due to the accidents of 
typhoid, three to hemorrhage, complicated with perforation in 
two instances, two to a combination of laryngitis and broncho- 
pneumonia, and one only to typhoid toxemia. It should be em- 
phasized in this connection that treatment was withheld in no 
case on account of the seriousness of the patient's condition, a 
fact of significance in considering the low mortality obtained. 
In two, at least, of our fatal cases the prognosis seemed inevitably 



234 TYPHOID FEVER 

fatal when treatment was begun. The treatment itself in these 
cases not only seemed to produce no further ill effect, but actually 
gave rise to a temporary benefit. 

The complications, again, were few in number, and only thir- 
teen in all in the entire ninety-eight cases (13.2 per cent). This 
means, not that thirteen cases showed complications, for there 
were indeed only eight cases which showed complications, but 
the total number of complications was thirteen. These com- 
plications were as follows: pyelitis one case, lobar pneumonia 
one case, laryngitis two cases, bronchopneumonia two cases, 
toxemia one case, hemorrhage four cases, perforation two cases. 
The percentage of hemorrhage (4%+) and of perforation (2%) 
is certainly below what may be expected as the usual averages 
for these complications, five to ten per cent for hemorrhage and 
three to four per cent for perforation. Although the earlier study 
of vaccine therapy in typhoid certainly led to the impression, 
particularly when the vaccine was administered subcutaneously, 
that complications were diminished (Krumbaar and Richardson, 
Callison), more recent work would seem to show that no distinct 
effect on the complications can be expected by the more recent 
intravenous type of treatment (Szecsy, Wiltshire and MacGilly- 
cuddy, Reiter, and Guinon and Malarte). 

The occurrence of relapses in this series of ninety-eight cases 
is of interest in connection with a supplementary type of vaccine 
therapy, to which Gay and Chickering referred in their com- 
munication. It is apparently the experience of several authors, 
including ourselves, that the intravenous vaccine therapy of 
typhoid fever, although it may lead to surprisingly successful 
results in shortening many cases of the disease, is of little value 
in preventing relapses. In our series of cases there were ten re- 
lapses (10.2%), which is approximately the number that might 
be expected. After experiencing several of these relapses we 
decided to follow up the intravenous therapy by a series of three 
subcutaneous injections of 0.1 milligram of the vaccine (800 
million bacteria), given on alternate days beginning at the point 
where the patient's temperature had remained normal for twenty- 
four hours. Thirty-seven cases in the latter part of our series 
have been treated in this manner and among them relapses oc- 
curred in only 5.39 per cent, whereas in sixty-nine cases in which 
the intravenous therapy was not followed by subcutaneous vac- 
cine injections the relapses occurred in 11.59 per cent. The same 
method of treatment has since been recommended by F. Meyer, 2 
Meyer and Altstaedt, and Wiltshire and MacGillycuddy. 



TREATMENT OF TYPHOID FEVER 235 

Non-Specificity of Vaccine Therapy in Typhoid 

It has become increasingly evident that the results produced 
by the administration of typhoid vaccine in typhoid fever can- 
not be regarded as specific in the narrower sense. The results, 
however striking they may be, are due primarily to the fact that 
a foreign protein has been injected more than to the fact that the 
foreign protein employed is a preparation of the causative agent 
in the disease in question. In the first place, it has been found 
that beneficial effects of a very similar nature and characterized 
by similar reactions to those described have been produced in 
typhoid fever by the administration of vaccines prepared from 
bacteria other than the Bacillus typhosus. Kraus was the first 
to note that he obtained beneficial results on the intravenous in- 
jection of colon as well as of typhoid vaccines. Ludke 3 and 
Lucksch both obtained results with colon vaccine, and the latter 
author obtained a favorable effect by gonococcus vaccines and 
by sodium nucleinate. Zupnik, Mliller and Leiner have utilized 
a vaccine made from the mouse typhoid bacillus as less toxic 
and as useful as true typhoid vaccine. Reibmayr, who has em- 
ployed colon and cholera vaccines in typhoid as well as typhoid 
vaccine, concludes that the former, although beneficial, are not 
as good as that derived from the specific microorganism. 

In a similar manner it has been found that other acute infec- 
tious diseases may be beneficially affected by the intravenous in- 
jection of their corresponding vaccines or of other vaccines. Thus, 
Kraus 2 notes the beneficial effect produced in cases of puerperal 
sepsis and pyocyaneus infections by the use of a colon vaccine. 
Rhein notes the beneficial effect in paratyphoid fever of typhoid 
vaccine. Nolf utilized peptone solutions advantageously in 
streptococcus infections. Miller and Lusk have employed ty- 
phoid vaccine by intravenous injection in acute, subacute and 
chronic arthritis with favorable results. 

This leads to a consideration of the less complex proteins and, 
indeed, simple inorganic salts that have been employed with 
claim to equally favorable results both in typhoid and in other 
acute infections. Ludke 3 has described the use of deutero-al- 
bumose in typhoid, Weichardt the employment of albumin solu- 
tions, and Nolf, as already mentioned, has used one-half a gram 
of peptone dissolved in 200 cubic centimeters of normal saline 
and administered intravenously. Baradulin has utilized dextrose 
solutions in considerable amount in cases of surgical sepsis, and 
Weichardt and Englander have obtained similar results with 



236 TYPHOID FEVER 

normal physiological saline alone. The use of colloidal gold 
(Colibiase) by Letulle and Mage, Barachon, Gay, Labb6 and 
Moussaud, and Delbet would seem simply another instance of 
the non-specificity of the reaction that we have described. 

It should be reiterated that in each and all of these instances 
the beneficial effects produced, which are undoubted, are brought 
about by the intravenous injections of a non-specific vaccine, a 
less complex protein, or even a complex or simple organic or in- 
organic substance. These injections, moreover, have all been 
followed by the train of symptoms we have described with ty- 
phoid vaccines, of chill, temperature excursion, and the results 
in the nature of critical recovery have been similar, though prob- 
ably differing in relative percentage. 

The Mechanism of Cure in Intravenous Vaccine Therapy 

This proof of the non-specificity of the most favorable results 
that can be produced by a typhoid vaccine in typhoid fever should 
not only not discourage us but lead us to inquire further into the 
mechanism of the reaction on which this benefit depends. In 
our work (Gay and Claypole, 4 Gay and Chickering) we have been 
led to attribute significance to two factors, which we believe not 
only concerned but of importance in the reaction which is pro- 
duced by intravenous vaccine injections. The first of these fac- 
tors is the hyperleucocytosis which following our observations 
has also been found to occur by a number of authors (McWilliams, 
Holler, Lowy, Lucksch and Wilhelm, Lucksch, Rohonyi, and 
Scully). It has also been shown that many of the substances 
which in a non-specific manner may lead to the same effects, 
as, for example, nuclein (Melnikowa and Wersilowa), and col- 
loidal gold (Busquet, Barachon, Letulle and Mage), also increase 
the leucocyte count, to which fact their results have been attrib- 
uted. 

As a second factor on which the degree of benefit obtained 
would seem to depend is the antibody content of the patient. 
This is indicated in the results cited in Table XXV, where it is 
found that the strength of the Widal titer seems to increase di- 
rectly with the benefit that results from injection. This observa- 
tion, moreover, would agree with the incidental observation 
of a number of observers that prognosis in general is more or less 
dependent on the strength of antibodies in the patient, and, 
particularly, that the prognosis of vaccine injection likewise bears 
some relation to the degree to which the individual has reacted 
against the infection. Of like significance is the extremely mild 



TREATMENT OF TYPHOID FEVER 237 

and favorable course of typhoid fever in the vaccinated. Koranyi 
has found that the opsonic index rises after vaccine injection in 
typhoid, and Inez Smith in our laboratory has apparently been 
able to demonstrate a distinct relation in the degree to which 
the opsonic index increases after intravenous injection and the 
result produced. In other words, the opsonic index rose much 
more markedly in the cases that were abortively cured than in 
either the benefitted or the unaffected cases. We have also fre- 
quently found that the agglutinin titer rises after the vaccine 
injection. 

Our hypothesis as to the mechanism by which cure was effected 
in the most striking instances has been, briefly, that it was due 
to a cooperation between the leucocytes that were called out by 
the injection and the antibodies already present in the patient, 
which latter substances acting as tropins caused the digestion and 
destruction of the typhoid bacilli in the body by the increased 
white blood corpuscles. There are several reasons for regarding 
this mechanism as probable apart from the now proved relation 
of the antibody strength and the leucocytic increase to the result 
obtained. In the first place, it can be shown by blood culture 
in some, though by no means all, instances that the bacteria 
disappear rapidly from the peripheral circulation following the 
injection. Similar results have been obtained by other inves- 
tigators. This working hypothesis may or may not be the cor- 
rect or ultimate explanation of the results produced by this non- 
specific reaction in typhoid fever and in other acute infections. 
There are other explanations which are probably no more ulti- 
mate and which, indeed, are not of necessity in any direct con- 
flict with the one we have presented. Jobling and Petersen have 
attributed the results produced by the reaction as due to a dis- 
turbance of ferment, antiferment balance, the antiferment being 
absorbed and the ferment being allowed to act. Similarly, Nolf 
speaks of a change in colloidal balance. This explanation is cer- 
tainly a very attractive one. Teague and McWilliams l ' 2 - 3 in 
recent experiments on rabbits also bring forth certain results 
which must be taken into consideration in explaining this type 
of therapy. They find that the injection of vaccine in rabbits 
produces a refractory condition which renders these animals 
temporarily more resistant to infection with the typhoid bacillus. 
They would attribute the results produced in the favorable cases 
of treatment to an overflowing of bactericidal substances, which 
are found to be present in the circulating blood, into the remoter 
lymph spaces which serve as metastatic foci in typhoid fever, 



238 TYPHOID FEVER 

and the consequent destruction of the bacteria that are present 
in them. 

It makes very little difference whether we regard the leucocytes 
or bactericidal ferments in the serum as the cause of the ultimate 
destruction of the bacteria, with which recovery seems to be as- 
sociated. It is probable, indeed, that the white blood cells are 
the source of the ferments, and we see no reason why these various 
factors and experiments that have been brought out by Teague 
and McWilliams, Jobling and Petersen and ourselves will not 
eventually stand in harmony in the ultimate explanation which 
may soon come. 

Since the cases in which the least favorable results are obtained 
seem characterized by the low antibody content in the serum, 
Gay and Chickering suggested that better results might be ob- 
tained in them by supplying the deficient antibodies by injec- 
tions of an artificial serum, and reported one or two cases in which 
a preparatory injection of the serum of a goat that had been im- 
munized by repeated injections of typhoid bacilli seemed to 
render the beneficial results secured by subsequent vaccine therapy 
more pronounced. Further limited experience with various 
antisera from goats prepared both by the injection of sensitized 
and of unsensitized living cultures (Gay 3 ) would not seem to 
give the anticipated result. The injection of an antityphoid 
serum of this sort may in itself produce a reaction similar to that 
evoked by vaccine (Etienne), and it is probable that the effect 
produced by Rodet and his collaborators, to which we have al- 
ready referred, is, in part at least, due to the fact that a foreign 
protein has been employed, since their results were better when 
the vaccine was given intravenously. The possibility, however, 
of a combined serum and vaccine therapy is one which we believe 
should be kept in mind and more extensively tested. 

Inasmuch as similar therapeutic results to those described 
following the use of typhoid vaccine can be obtained by the in- 
travenous injection of almost any protein substance, the question 
may well be asked as to whether there is any advantage in using 
typhoid vaccine rather than some other substance. We believe 
that a typhoid vaccine, particularly of the type we have recom- 
mended, possesses distinct advantages over other proteins. Such 
a vaccine, as we employ it, is easily kept indefinitely in dried 
form and under conditions of strict asepsis, and can readily be 
introduced in exact amounts. Typhoid vaccine, further, has 
the advantage over other protein preparations of building up 
the active immunity of the patient, and a sensitized vaccine 



TREATMENT OF TYPHOID FEVER 239 

will in our experience produce a higher grade of leucocytosis. It 
is evident from remarks we have made that in our own experience 
the use of typhoid vaccine intravenously is attended by no real 
danger and is contraindicated in only those few cases of typhoid 
fever which are complicated by some profound functional dis- 
turbance of the heart. The very few individuals who have been 
led through unfortunate experience to discontinue the intra- 
venous injection of vaccines, Peutz, Sladek and Kotlowsky, and 
Deutsch, treated very few cases, and the dangers which they 
report must be attributed to their inexperience and the excessive 
amount of vaccine employed. We regard, then, the intravenous 
vaccine treatment of typhoid fever as the most effective type 
of therapy hitherto devised to combat this disease. It would 
seem indicated in nearly every case and at any time during the 
febrile period. It would seem, moreover, likely that further in- 
vestigation will enhance the value of this type of therapy. 



CHAPTER XIV 

SUGGESTED METHODS OF ADVANCE IN SOLVING THE 
TYPHOID PROBLEM 

An attempt has been made in this treatise to express the present 
status of our effective knowledge concerning typhoid fever. Mat- 
ters of apparently purely theoretical interest have been treated 
as fully as those with a practical application, with an appreciation 
of the fact that such theoretical knowledge will eventually serve 
directly or indirectly in the practical advances that are to come. 
It is evident that increasing knowledge of the mechanism by 
which typhoid fever propagates itself, both within and without 
the human body, has given us increasing power to diminish the 
incidence of the disease. As we have shown, both the morbidity 
and mortality rates from this disease have been enormously re- 
duced, and the reduction continues. This reduction in the in- 
cidence of typhoid fever in the larger centers of population is due 
largely to the appreciation and enforcement of sanitary measures 
carried out with a thorough knowledge of the life cycle and dis- 
tribution of the typhoid bacillus. In smaller groups the more 
recent and effective advance has been in the matter of immuniza- 
tion in conjunction with the ordinary sanitary precautions. Vac- 
cination against typhoid, although extremely effective in segre- 
gated and particularly in completely immunized units, has not 
so far exerted a fundamental effect on the total morbidity rate 
from the disease. The advances that have been made in the 
suppression of typhoid fever cannot but awaken confidence and 
enthusiasm in the effectiveness of preventive medicine. These 
advances have been so marked in the case of this disease that we 
may confidently look forward to its eventual suppression. This 
suppression will be brought about both through the consistent 
application of measures arising from the knowledge we already 
possess as to the pathogenesis and transmission of typhoid fever, 
and through the acquisition of further knowledge of certain as- 
pects of the disease. It is the purpose of these closing paragraphs 
to attempt to outline certain paths along which may come 
these advances in our knowledge of typhoid fever and in its 
control. 

240 



METHODS OF SOLVING THE TYPHOID PROBLEM 241 



THE DIAGNOSIS OF CASES OF TYPHOID FEVER 

One of the most important factors in preventing the extension 
of typhoid fever lies in the early detection of each individual case. 
The methods of diagnosis of typhoid fever are so highly perfected 
that diagnosis can be made at least in the earliest days of the dis- 
ease, and, indeed, might be made in the incubation period of the dis- 
ease, if suspicion were directed toward the individual in question. 
The early diagnosis of typhoid fever depends not only on the co- 
operation of the laboratory with the practitioner of medicine, 
but on the willingness and initiative of the practitioner in availing 
himself of such cooperation as is available. It should be the func- 
tion of the laboratory not only to accede to the demands of the 
practitioner but to suggest methods of which the practitioner 
might and should avail himself. In every well organized commun- 
ity facilities are at hand for the free diagnosis of blood samples by 
means of the agglutination test for typhoid fever. These means 
are made use of by all well informed practitioners and their aid 
in diagnosis and in protecting the public health is very great. The 
early diagnosis of the disease is obtained, however, as we have 
shown, more surely by means of blood cultures, and this method 
of diagnosis is by no means as available as it should be for the 
general practitioner. The practitioner has usually neither the 
experience nor the facilities for making and particularly for study- 
ing blood cultures, and it should be the duty of every municipal 
and state laboratory to afford greater facilities, not only for the 
detection of the typhoid bacillus in blood cultures, but for the 
actual taking of the cultures themselves. A simple extension of 
the district nurse system, in cities at least, would provide for this 
deficiency in the diagnostic aid that is furnished by state and 
municipal laboratories. A trained nurse could readily be in- 
structed in the complete technique of obtaining and diagnosing 
blood cultures, and the additional expense to the community would 
be inconsiderable. 

THE MANAGEMENT OF CARRIERS 

We have sufficiently emphasized the importance of carriers as a 
means of the further extension of typhoid fever. This method of 
extension is due in large part to the fact that carriers are unsus- 
pected. If all carriers of typhoid bacilli were known, the first and 
most important step would be made in preventing the genesis of 
secondary cases from this important source. Every effort should 



242 TYPHOID FEVER 

be made, particularly in densely populated communities, to obtain 
as complete a registration of carriers as may be possible. This may 
be effected in several ways. In the first place, every recovered case 
of typhoid fever should have several negative stool examinations 
before being discharged as healthy. Provision should be made so 
that such examinations may be carried out not only in hospitals, 
where at present they are infrequently performed, but also in 
private cases through cooperation between the attendant physician 
and municipal laboratories. Recovered cases that remain car- 
riers would thus be detected and recognized. Their recognition 
would in most cases in no way interfere with their personal liberty, 
but would make it possible for a central laboratory to keep in touch 
with them. Careful instruction should then be given to all such 
carriers and every effort made to teach them to appreciate their 
potential danger to the community. If such carriers would sign 
an agreement to report to the central laboratory for examination, 
their eventual freedom from typhoid bacilli might be determined. 
More important still, their relation to any further cases of the 
disease would be promptly discovered and means taken to prevent 
additional infection. Legal measures should be available to en- 
force the compliance of these recovered carriers with such rules 
as may be laid down for their conduct, and isolation, even, should 
be possible in recalcitrant or careless individuals. 

Thorough-going search for and registration of all recovered car- 
riers will lead eventually to the complete census of all sources of 
further infection in this category. Such methods, however, will 
not aid in the detection of carriers who have come from less closely 
guarded communities, or of the healthy carriers in a most carefully 
checked community, such as we have outlined. We have already 
expressed the difficulty or impossibility of detection of all carriers 
in any general community by the laborious methods of stool 
examination which at present are necessary to find them. It is 
increasingly evident that some easier method of detecting typhoid 
carriers is highly desirable. So far, the only possible test pointing 
to possible carriers rests on a positive Widal reaction, which, how- 
ever, is not present in all carriers and is positive in many who are 
not carriers. The suggestion is made that the possibility of em- 
ploying the typhoidin test for the purpose of detecting healthy 
and recovered carriers should be investigated. 

Most important from the public standpoint, next to the detec- 
tion of carriers, and more important still from the individual 
standpoint, is some means of treating them effectively. We have 
fully considered how inadequate all suggested methods of cure 



METHODS OF SOLVING THE TYPHOID PROBLEM 243 

have been. Further study of the rabbit carrier condition, which 
presents so close an analogy to the human carrier, is obviously in- 
dicated. The possible use of chemotherapeutic means of effecting 
this end by studying the elimination of various dye stuffs and 
chemical substances through the liver and bile have already sug- 
gested certain studies with this purpose in view, and definite 
progress may soon be made in the direction of some specific method 
of curing the carrier condition. 

IMMUNIZATION AGAINST TYPHOID FEVER 

Further practical advances are possible in methods of vaccina- 
tion against typhoid fever, and theoretical studies as to the nature 
of the immunity produced by vaccination will doubtless serve 
toward these advances. We may well question why the protec- 
tion afforded by vaccination in recognized manners against 
typhoid fever is less durable than that accomplished through re- 
covery from the disease. We have already outlined the differences 
in the expression of this immunity in the blood serum in the two 
instances and expressed the opinion that recovered typhoid 
immunity is cellular, whereas artificial typhoid immunity is to a 
large extent humoral in nature. The exact nature of this durable 
cellular immunity acquired through recovery is by no means under- 
stood, and an intensive comparative study of the tissues in re- 
covered typhoid cases as compared with those vaccinated against 
typhoid and with normal individuals might afford some informa- 
tion in this direction. If it could be demonstrated, for example, 
that certain tissues of recovered typhoid cases, perhaps the tissues 
of the lymphatic system, contain cellular antibodies in contradis- 
tinction to normal tissues, great insight as to the nature of this 
durable immunity would be gained. Whether it is possible to 
produce a fundamental immunity of this sort by artificial means is 
extremely doubtful, but at least an appreciation of the differences 
between this type of immunity and that afforded by vaccination 
might be expected to aid in further perfecting the latter process. 

Every effort should be made to stimulate typhoid vaccination 
in the general community. This may be brought about by prop- 
aganda of various sorts and by the free distribution of vaccine by 
municipal, state or even federal laboratories. The inclusiveness of 
vaccination would seem to increase its efficiency, and every effort 
should be made to create a typhoid vaccinated community in such 
a manner as has been done in the case of small-pox. 

In addition, further investigation is desirable as to the duration 



244 TYPHOID FEVER 

of protection by any method in vogue. We have already suggested 
the value of the typhoidin test as indicating the failure of individ- 
uals to respond sufficiently to the vaccine to ensure normal protec- 
tion, and some systematic method of applying this test, if it proves 
as reliable as we have anticipated, should be considered. 



TREATMENT OF TYPHOID FEVER 

The greatest progress that has been made in the treatment of 
typhoid fever would seem to be in connection with the protein 
reaction produced by the intravenous injection not only of typhoid 
vaccine, but of other protein substances. The nature of this reac- 
tion is to some extent understood. The relation of leucocytes to 
the process and the stimulation or mobilization of antibodies 
induced by this means are recognized. Of the theories that have 
been advanced to explain the beneficial results that not infre- 
quently follow this injection of foreign protein, the most attractive 
would seem to be that of Jobling and Petersen, which is fully in 
harmony with the ideas of Nolf and others as to fluctuations in the 
colloidal balance between ferment and antiferment. It would seem 
desirable, not only for practical ends in connection with protein 
therapy of this type, but for the purpose of theoretical knowledge 
that better methods of detecting and complete demonstration of 
the presence and nature of such ferments should be available. 
It is particularly desirable from the standpoint of general con- 
siderations of immunity that further knowledge should be ob- 
tained as to the relation of ferments of this sort to recognized types 
of antibodies that have been more circumstantially studied. 



BIBLIOGRAPHICAL INDEX OF REFERENCES QUOTED 

(The references are given alphabetically by authors. Where several references 
to a given author occur, they are cited in order of their occurrence in the 
text. Any reference in the text without a number refers to the first 
reference given under that author's name. Subsequent references are 
numbered consecutively.) 

Achard, Ch., and R. Bensaude. Infections paratyphoidiques. Bull, et 
mem. de med. d. hop., Paris, 1896, xiii, 820. 

Achard, Ch., and Ch. Foix. Sur Femploi des corps gras comme vehicules 
des vaccins microbiens. Compt. Rend. Soc. Biol., 1916, lxxix, 209. 

Albert and Mendehall. Reactions induced by antityphoid vaccina- 
tion. Am. Jour. Med. Sciences, 1912, cxliii, 232. 

Aldershoff, H. De beteekenis der reactie van Gruber-Widal voor de 
diagnose "febris typoidea bij de ingeenten." Nederlandsch. Tijd- 
schrift voor Geneeskunde, 1916, II, 284. 

Altstaedt. Zur Typhusimmunitat. Berl. klin. Woch., 1915, lii, 681. 

Alvarez, B. G. Vinegar-water and acid wines in treatment of typhoid 
and paratyphoid. Siglo Medico, Madrid, 1917, lxiv, 2. (Jour. Am. 
Med. Asso., 1917, Mar. 17, p. 885.) 

Andriescu, Ch. and M. Ciuca. De Taction du s6rum antityphique de 
Besredka sur revolution de la fievre typhoide. Ann. Inst. Past., 1913, 
xxvii, 170. 

Antityphoid Committee (Great Britain), Report of the. T. Fisher 
Unwin, London, 1913. 

Aoki, K. Uber die Komplementbindungsreaktion und die hamoly- 
sehemmende Wirkung des Serums bei Bazillentragerkaninchen. 
Zeitsch. f. Immunitatsforsch., 1913, xix, 354. 

Archibald, R. G., G. Hadfield, W. Logan and W. Campbell. Reports 
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troops in the Dardanelles. Jour. Royal Army Med. Corps, June, 1916. 

Ardin-Delteil, L. Negre and M. Raynaud. (1) Recherches sur les 
reactions humorales des malades atteints de fievre typhoi'de trait^s 
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371. 

(2) Sur la vaccinothe>apie de la fievre typhoi'de. Comp. Rend. 
Acad. Sciences, 1912, cxl, 1174. 
245 



246 BIBLIOGRAPHICAL INDEX 

Arima, R. (1) Ueber die Typhustoxine und ihre pathogene Wirkung. 
Cent. f. Bakt., 1912, lxiii, 424. 

(2) Ueber Antikorperbildung gegen Typhustoxine. Cent. f. Bakt., 
1912, lxv, 183. 

Aronson, Hans. Untersuchungen uber Typhus mit Typhusserum. 
Berl. klin. Woch., 1907, No. 18, 572. 

Ascoli, M. (1) Die spezifische Myostagmin Reaktion. Miinch. med. 
Woch., 1910, lvi\ 

(2) Essai de diagnostic de la fievre typhoide au moyen de l'anaphy- 
laxie passive. Compt. rend. Soc. Biol., 1908, lxv, 611. 

Ast, Fritz. Praktische Erfahrungen mit der serodiagnostischen Typhus- 
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2634. 

Atlassoff, J. La fievre typhoide experimentale. Ann. Inst. Past., 1904, 
xviii, 701. 

Auche, B. and P. Chevalier. Un cas d'insuccSs de la vaccination anti- 
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Austrian and Bloomfield. The typhoidin reaction. Arch. Int. Med., 
1916, xvii, No. 5. 

Bachmeister. Der Ausfall des Cholesterins in der Galle und seine 
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Baerthlein, K. Ueber die Mutation bei Bakterien und die Technik zum 
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Bagltvi. Opera omnia. Romae, 1696. 

Baillie. Plates of morbid anatomy. Fasc. 4, p. ii, Fig. 3. 

Bainbridge, F. A. The Milroy lectures on paratyphoid fever and meat 
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Ballard, E. On a localized outbreak of typhoid fever in Islington during 
the months of July and August, 1870, traced to the use of impure 
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Balthazard, V. Toxine typhique et antitoxine typhique. J. B. 
Bailliere et Fils, 1903. 

Bandi. Contributo alio studio del tifo sperimentali. Ufficiale sanitorio, 
1889, 145 and 193. 

Banti, G. Sulla localizzazioni atipichi della infezione tifosa. Riforma 
med., 1887, Oct. (Cit. Baumgarten, 1888, iv, 148.) 

Barabaschi, P. Importanza dei vermi intestinali nella infezioni di 
febbre tifioide. Gazz. d. Ospedali e d. Clin., 1910, No. 25. 



BIBLIOGRAPHICAL INDEX 247 

Bakachon. L'or colloidal comme adjuvant dans le traitement des 
6tats typhoides. Paris, meU, 1916, vi, 570. 

Baradulin, G. I. Intravenous infusion of hypertonic solution of grape 
sugar in treatment of purulent processes. Rusksy Vratch., 1916, xv, 
833. (Jour. Am. Med. Asso., 1916, Nov. 25, 1636.) 

Barlow. On the distinction between typhus fever and dothienenterie. 
Lancet, 1840, Feb. 29. 

Bartlett, Elisha. The history, diagnosis and treatment of the fevers 
of the United States. Blanchard & Lea, Phila., 1856. 

Battlehner, R. Uber Latenz von Typhusbacillen im Menschen. Diss., 
Strassburg, 1910. 

Baumler. Typhusbazillen in den lymphatischen Apparaten des Darmes. 
Internat. Hyg. Kongress, 1907. (Cent. f. Bakt., Ref. I. Abt., 1908, 
xli, 230.) 

Baur, J., P. Abrami and J. Stevestre. La vaccination antitypho- 
paratyphique. Soc. Med. des Hop., 1916, Mar. 3. (La Presse MeU, 
1916, Mar. 9.) 

Baur, J., Hautefeuille and J. Stevestre. Germes specifiques dans 
les vomissements bilieux au cours des maladies typhoides. Soc. 
MeUcale des Hopitaux, 1916, Jan. 28. (Presse Med., 1916, Feb. 3, 
No. 7, 56.) 

Bech. Fievre typhoide. Reunion meU chir. de la Ire. Arm6e, 1916, 
Jan. and Feb. (Presse MeU, 1916, Apr. 17.) 

Bergell and Meter. Uber eine neue Methode zur Herstellung von 
Bakterien-Substanzen, welche zur Immunisierungszwecken geeignet 
eind. Med. Klin., 1906, 16. 

Berget, D. H. The pyrogenic action of bacillus typhosus. Jour. Med. 
Res., 1915, xxxi, 433. 

Bernard, L. Les formes legeres de la dothienenterie et l'embarras 
gastrique febrile. Ann. de MeU, 1916, iii, 32. 

(2) Les infections typhoides et la vaccination antityphoide. Bull. 
Acad. MeU, 1915, Sept. 28, 336. 

Bernard, L. and J. Paraf. Statistiques des infections typhoides chez 
les sujets vaccinas contre la fievre typhoide. Presse MeUcale, 1915, 
Oct. 11, 399. 

(2) Les infections typhoides chez les sujets vaccinas contre la 
fievre typhoide. Ann. de MeU, Paris, 1915, Oct. No. 5. 

Bhbredka, A. Etudes sur le bacille typhique et le bacille de la peste. 
Ann. Inst. Past., 1905, xix, 477. 

(2) De rimmunisation active contre la peste, le cholera et l'infec- 
tion typhique. Ann. Inst. Past., 1902, xvi, 918. 



248 BIBLIOGRAPHICAL INDEX 

(3) Deux ans de vaccination antityphiques avec du virus sen- 
sibilise vivant. Ann. Inst. Past., 1913, xxvii, 607. 

(4) De l'anti-endotoxine typhique et des anti-endotoxines en 
general. Ann. Inst. Past., 1906, xx, 449. 

Beumer and Peiper. Bakteriologische Studien iiber die atiologische 
Bedeutung der Typhusbazillen. Zt. f. Hyg., 1887, II, 110. 

Bezancon, F. and A. Philibert. Formes extraintestinales de l'infection 
eberthienne. Jour, de Phys. & Path, generate, 1904, vi, 74. 

Bezzola, C. and Vallardi. Contributo alia conoscenza della immunita 
antitifica naturale. Pathologica, 1912, iv, 353. 

Biedl, A. Zur Vakzinetherapie des Typhus abdominalis. Letter to 
Paltauf in Wien. klin. Woch., 1915, xxviii, 125. 

(2) Therapeutische Verwendung von Typhus-Impstoffen beim 
Menschen. Prag. med. Woch., 1915, xl, 53. 

Bierast, W. Ueber das Bierastische Petrolaetherverfahren zum Nach- 
weis des Typhus und Paratyphuskeimes in Stuhl. Berl. klin. Woch., 
1916, May 15, 532. 

Billet, A., LeBihan, F., Therault, Lamande, Lutrot and Louis, J. F. 

L'epidemie de fievre typhoide dans la garnison de St. Brieuc en 1909. 

Arch, de Med. & Pharm. MUit., 1910, lv, 281. 
Bindseil. Bakteriologischer Sektionbefund bei einem chronischen 

Typhusbazillentrager. Zeit. f. Hyg., 1913, lxxiv, 369. 

Blachstein, O. G. Intravenous inoculation of rabbits with Bacillus coli 

communis and the Bacillus typhi abdominalis. Bull. Johns Hopkins 

Hosp., 1891, ii, 96. 
Blandini, P. Profilassi specifica del tifo abdominale. Ann. d'igiene 

sperimentale, 1905, xv, 295. 
Blassberg, M. Positive Typhusbazillenkultur und Typhusagglutina- 

tion bei Miliartuberkulose. Wien. klin. Woch., 1915, xxviii, 1314. 

Blumenthal, Ernst. Ueber das Auftreten von Typhusbacillen in den 
Gallenwegen nach intravenoser Injektion. Cent. f. Bakt., 1910, lv, 
341. 

Blumenthal, Franz. Ueber das Vorkommen von Typhus and Para- 
typhus Bazillen bei Erkrankungen der Gallewegen. Miinch. med. 
Woch., 1904, 1641. 

Boehncke, K. E. Die Vaccina tionsprophylaxe und Therapie des 
Abdominal typhus. Med. Klinik, 1913, ix, 1690. 

Bohne, A. Vergleichende bakteriologische Blut-, Stuhl- und Urinunter- 
suchung bei Typhus abdominalis. Zeit. f. Hyg., 1908, lxi, 213. 

Boinet. Vaccinothe'rapie de la fievre typhoide par le virus sensibilise" de 
Besredka. Compt. Rend. Soc. Biol., 1913, lxxiv, 507. 



BIBLIOGRAPHICAL INDEX 249 

Boldtjan, C. and W. C. Noble. A typhoid bacillus carrier of forty-six 
years standing, and a large outbreak of milk-borne typhoid fever 
traced to this source. Jour. Am. Med. Asso., 1912, lviii, 7. 

Bonhoff and Tsuzuki. Uber die Schnellimmunisierungsmethode von 
Fornet und Miiller. Zeit. f. Immunitatsforsch., 1910, iv, 180. 

Boral, H. Beitrag zur Frage der Typhustherapie mit Besredkas Vakzine. 
Wien. klin. Woch., 1915, xxviii, 415. 

Bokdet, J. Les leucocytes et les propri6t£s actives du serum chez les 
vaccinas. Ann. Inst. Past., 1895, ix, 462. 

Bordet, J. and 0. Gengou. Sur l'existence de substances sensibilisatrices 
dans la plupart des serums antimicrobiens. Ann. Inst. Past., 1901, 
xv, 290. 

Botez, A. Le violet de methyle comme moyen de differenciation dans la 
serie typhi-coh. Reun. biol. Bucarest, 1915, July 8. (Compt. Rend. 
Soc. Biol., 1915, lxxviii, 489.) 

Bourges, H., R. Lancelin and P. R. Jolly. Septicemics a microcoques 
(diplococcemies). Soc. M6dicale des Hop., 1915, Dec. 10. 
(2) Infections a F aspect chnique typho'ide realisees par la presence 
constante d'un microcoque dans le sang. Soc. de Biol., 1915, 
Dec. 4, 692. 

Bourke, Evans and Rowland. Autogenous living vaccine in the treat- 
ment of enteric fever. British Med. Jour., 1915, Apr. 3. 

Boycott, A. E. Observations on the bacteriology of paratyphoid fever 
and on the reactions of typhoid and paratyphoid sera. Jour, of Hyg., 
1906, vi, 33. 

Brand, E. Die Hydrotherapie des Typhus. Stettin, 1861. 

Braun, H. and M. Feiler. Ueber Serumfestigkeit des Typhusbacillus. 
Zeit. f. Immuniz., 1914, xxi, 447. 

Bretonneau. Notice sur la contagion de la dothienenterite. Arch. gen. 
de meU, 1829, xxi, Ser. 1. 

Brieger, L. Weitere Untersuchungen iiber die Ptomaine. Berlin, 1883. 

Brieger, L., S. Kitasato and A. Wassermann. Ueber Immunitat und 
Giftbestigung. Zeit. f. Hyg., 1892, xii, 137. 

Brieger, L. and Mayer. Weitere Versuche zur Darstellung spezifischer 
Substanzen aus Bakterien. Deut. med. Woch., 1913, 309. 

Brion, A. and H. Kayser. Neue klinische bakteriologische Erfahrungen 
bei Typhus. Deut. Arch. f. klin. Med., 1906, lxxxv, 552. 

Bronner, C. E. C. Typhusschutzimpfung und Typhusdiagnose bei 
Geimpften. Medizin. Klinik, Berlin, 1915, xi, 959. 



250 BIBLIOGRAPHICAL INDEX 

Brouardel, P. and L. Thoinot. Fievre typhoide. J. B. Bailliere et Fils, 
Paris, 1905. 

Broughton-Alcock, W. Vaccination for typhoid fever with living 
sensitized bacilli. Lancet, 1913, July 12, p. 104. 

Brown, H. C. Standardization of vaccines. Indian Jour. Med. Res., 
1914, I, 71. 

Bruce, D. Analysis of the results of Professor Wright's method of anti- 
typhoid inoculation. Jour. Roy. Army Med. Corps, 1905, iv, 241. 

Bruckner, G. Ueber Typhusverbreitung. Deut. med. Woch., 1912, 
Aug. 8, 1490. 

Budd, W. On intestinal fever: its mode of propagation. Lancet, 1856, 
ii, 618, 694. 

(2) Typhoid fever: its mode of spreading and prevention. London, 

Longmans, Green & Co., 1873. 

(3) Outbreak of fever at the Clergy Orphan School, St. Johns Wood. 

Lancet, 1856, Nov. 15. 

(4) On the fever at the Clergy Orphan School, St. Johns Wood. 

1856, Dec. 6. 

Bujioid, O. Die Erzeugung der Impstoffe und Massenimpfungen im 
Krakau gegen Cholera und Typhus in der Zeit des Krieges. Med. 
Klin., 1915, xi, 1421. 

Busquet, H. Etude experimental sur Tor colloidal. Presse M6d., 1915, 
Sept. 16, No. 43, 356. 

Busse, O. Ueber das Vorkommen von Typhusbazillen im Blute von nicht 
typhuskranken Personen. Munch, med. Woch., 1908, No. 21, 294. 

Cade and Vaucher. Les reactions agglutinantes dans les infections 
typho'idiques et paratphoidiques. Ann. de M£d., 1916, iii, 222. 

Callison, J. G. Therapeutic use of vaccines in typhoid fever. Am. Jour. 
Med. Sci., 1912, cxliv, 350. 

Calmette and Salimbeni. La peste bubonique. Etude de l'epidemie de 
Oporto en 1899. Ann. Inst. Past., 1899, xiii, 865. 

Cammaert, C. A. Typhoid among Belgian refugees in Holland. Neder- 
landsch Tijdschrift v. Geneeskunde, Amsterdam, Mar. 4, No. 10. 
(J. Am. M. A., Apr. 22, 1916.) 

Canstatt, C. F. Spezielle Pathologie und Therapie von klinischen 
Standpunkte ausbearbeitet. 3d ed. Enke, Erlangen, 1855. 

Capaldi and Proskauer. Beitrag zur Kenntnis der Saurebildung bei 
Typhusbacillen und Bacterum coli. Zeit. f. Hyg., 1896, xxiii, 452. 

Carnot, P. and B. W. Weill-Halle. Notes pratiques sur la recherche 
du bacille typhique dans l'organisme. La Presse M6d., 1915, xxiii, 89. 






BIBLIOGRAPHICAL INDEX 251 

Caronia, G. Improved technique for vaccination against typhoid and 
paratyphoid. Pediatria, Naples, 1917, Jan., No. 1, 1. (Quoted in 
Jour. Am. Med. Asso., 1917.) 

Carpano, M. Ueber die Kapselhulle einiger Bakterien. Cent. f. Bakt., 
1913, Ixx, 42. 

Castellani, A. On hemolysins produced by certain bacteria. Lancet, 
1902, Feb. 16, 440. 

(2) Sul reperto del bacillo tifico nel sangue. Riforma medica, 

1899, I. 

(3) Die Agglutination bei gemischter Infection und die Diagnose 
der letzteren. Zeit. f. Hyg., 1902, xl, 1. 

(4) Observation on typhoid vaccination in men with attenuated 
living cultures. Cent. f. Bakt., 1909, lii, 92. 

(5) Typhoid and paratyphoid vaccination with living attenuated 
vaccines. Lancet, 1912, Mar. 1, No. 4679, 583. 

(6) Note on typhoid-paratyphoid vaccination with mixed vaccines. 
Cent. f. Bakt., 1914, lxxii, 536. 

(7) Typhoid-paratyphoid vaccination with mixed vaccines. Brit. 
Med. Jour., 1913, ii, 1577. 

(8) Further remarks on the mixed typhoid and paratyphoid A and 
paratyphoid B vaccine. Brit. Med. Jour., 1915, May 1, 758. 

(9) Further researches on combined vaccines. Cent. f. Bakt., 1915, 
lxxvii, 63. 

(10) Brief note on a case of triple infection: typhoid, paratyphoid A 
and paratyphoid B. Jour. Trop. Med. and Hyg., 1915, xviii, 
37. 

Chamberlain, W. P. Care of troops on the Mexican border. Jour. Am. 
Med. Asso., 1916, Nov. 25, 1573. 

Chantemesse, A. L'opthalmo diagnostique de la fievre typhoide. Bull. 
Acad, de MeU, 1907, 1384. 

(2) Toxine typhoide soluble et s6rum antitoxique de la fievre 
typhoide. Prog, med., 1898, vii, 245. 

(3) Resultats de la vaccination antityphoidique dans la marine 
francaise. Bull, de lAcad. de MeU, 1916, lxxxvi, 140. 

(4) Sur la vaccination antityphoide. Bull, de lAcad. de MeU, 

1911, lxvi, 347. 

(5) Sur le vaccin triple de la fievre typhoide. Presse M6d., 1915, 
Sept. 2. 

(6) Vaccinoth^rapie de la fievre typhoide. Bull. Acad, de MeU, 

1913, lxix, 493. 

Chantemesse and Widal. De rimmunite" contre le virus de la fievre 
typhoide, conferee par des substances solubles. Ann. Inst. Past., 
1888, II, 54. 

Chapin, C. V. The sources and modes of infection. 2d Ed. Wiley and 
Sons, 1912. 



252 BIBLIOGRAPHICAL INDEX 

Charrin, M. and H. Roget. Note sur le deVeloppement des microbes 
pathogenes dans le se'rum des animaux vaccines. Compt. Rend. Soc. 
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Chiari, H. Ueber atypische Formen des Typhus abdominalis. Bericht 
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viii, 790. 

(2) Ueber Cholecystitis typhosa. Prag. med. Woch., 1893, xvii, 

261. 

(3) Ueber das Vorkommen vod Typhusbazillen in der Gallenblase 
bei Typhus abdominalis. Cent. f. Bakt., 1894, xv, 648. 

(4) Ueber Typhus abdominalis und Paratyphus in ihnen Bezie- 
hungen zu den Gallenwegen. Verhand. de deutsch. path. 
Ges., Dresden, 1907. 

Chirolanza, R. Experimentelle Untersuchungen liber die Beziehung 
der Typhusbacillen zu der Gallenblase und den Gallenwegen. Zeit. f . 
Hyg., 1909, lxii, 11. 

Chomel, A. F. Lecons de clinique medicale, I. Fievre typhoiide. Paris, 
1834. 

Ciuca, M., D. Combiescu and J. Balleanu. Deux epidemies de fievre 
typhoide; vaccinations antityphiques au virus sensibilise" vivant de 
Besredka. Ann. Inst. Past., 1915, xxix, 105. 

Clarke, C. The presence of B. typhosus in the blood during relapses in 
enteric fever. Jour. Roy. Army Med. Corps, 1915, xxv, 333. 

Cler, E. and A. Ferazzi. Sulla presenza del bacillo di Eberth nelle feci 
di individui sani. Scritti med. in onore di C. Bozzolo, Torinese, 1904. 
(Cent. f. Bakt., Ref. 1905, xxxvi, 479.) 

Cole, R. Typhoid fever. Practical Treatment, Musser & Kelly, 1911, II. 

Coleman, W. The high calory diet in typhoid fever ; a study of 1 1 1 cases. 
Am. Jour. Med. Sci., 1912, cxliii, 77. 

(2) Diet in typhoid fever. Jour. Am. Med. Asso., 1909, liii, 1145. 

(3) Weight curves in typhoid fever. Am. Jour. Med. Sci., 1912, 
cxliv, 659. 

(4) The influence of the high calory diet on the course of typhoid 
fever. Jour. Am. Med. Asso., 1917, lxix, 329. 

Coleman, W. and B. H. Buxton. The bacteriology of the blood in 
typhoid fever cases. Am. Jour. Med. Sci., 1907, cxxxiii, 896. 

Coleman, W. and Dubois. Calorimetric observations on the metabolism 
of typhoid patients with and without food. Arch. Int. Med., 1915, 
xv, 887. 

Collings, H. A. A reasonable treatment for typhoid. Calif. State Jour, 
of Med., 1915, xiii, 69. 



BIBLIOGRAPHICAL INDEX 253 

Conn, H. W. The outbreak of typhoid fever at Wesleyan University. 
Report Bd. of Health of Conn., New Haven, 1895, xvii, 243. 

Conradi,* H. (2) Zur Frage der ragionaren Typhusimmunitat. Klin. 
Jahrb., 1907, xvii, 273. 

(3) Ein Verfarhen zum Nachweis sparlicher Typhusbacillen. 
Cent. f. Bakt., Ref., 1908, xlii, Beihefte, 47. 

(4) Quoted from Ledingham and Arkwright, q. v. 

(5) TJeber sterilisierende Wirkung des Chloroforms in Tierkorper. 
Zeit. f. Immunitatsforsch., 1910, vii, 158. 

(6) Ueber losliche, durch aseptische Autolyse erhaltene Giftstoffe 
aus Ruhr- und Typhusbacillen. Deut. med. Woch., 1903, No. 2. 

Conradi,* J. Warm steckt der Typhuskranke an. Deut. med. Woch., 
[t 1907, Oct, 10, 1684. 

Courmont, P., Chattot and Pierret. Le serodiagnostique des para- 
typholdes. Soc. med d. Hop., 1916, June 9. 

Courmont, P. and Rochatx. Immunisation antityphique de Thomme 
par voie intestinal. Comp. Rend. Acad, des Sci., 1912, cliv, 1829. 
(2) Etudes experimentales sur la vaccination antityphoidique. 
Ann. Inst. Past., 1917, xxxi, 187. 

Coyon, A. and L. Rivet. Etude sur 66 cas de paratypho'ide. Presse 
MSdicale, 1915, Oct. 14. 

Csernel, E. and A. Marton. Die Therapie des Abdominaltyphus mit 
nicht sensibilisierte Vakzine. Wien. klin. Woch., 1915, xxviii, 229. 
(2) Die Behandlung des Typhus abdominalis mit nicht sensibilis- 
ierte Vakzine. Wien. klin. Woch., 1915, No. 27, 733. 

Crombie. Some statistics regarding the effect of inoculation against 
typhoid fever in South Africa. Lancet, 1902, May 3. (Fornet: 
Kolle & Wassermann, III, 894, ref. 297.) 

Cummins, W. T. and P. K. Brown. Atypical typhoid infection. Arch. 
Int. Med., 1913, Oct. 

Currie. Medical reports on the effects of water as a remedy in fever. 
London, 1797. 

Curschmann. Typhoid fever and typhus fever. W. B. Saunders & Co., 
Phila., 1902. 

Cushing, Harvey. Typhoidal cholecystitis and cholelithiasis. Johns 
Hopkins Hosp. Bull., 1898, ix, 91. 

Dakeyne, D. I. Agglutination reactions of blood of soldiers inoculated 
against typhoid. Lancet, London, 1915, II, 529. 

Danysz, J. Un microbe pathogene pour les rats. Ann. Inst. Past., 1900, 
xiv, 193. 

♦Conradi in text without number refers to J. Conradi. 



254 BIBLIOGRAPHICAL INDEX 

Daumezon, G. Bacille paratyphique aberrant, isole* du sang. Bull. 
Acad. Med., 1915, April 27, 489. 

(2) Sur la flore typhique et paratyphique du liquide cephalo- 
rachidien. Bull. Acad. Med., Aug., 1915, 123. 

Davis, L. Antityphoid vaccination. Jour. Am. Med. Asso., 1912, 
lviii, 537. 

Davison, W. C. Report on prophylactic vaccination with Bacillus 
typhosus, Bacillus para typhosus A and Bacillus para typhosus B. 
Jour. Lab. & Clin. Med., 1917, II, 607. 

Dawson, G. D. Diagnosis of typhoid fever in inoculated subjects. 
Brit. Med. Jour., 1915, July 24. 

Decobert, C. Du gelo-diagnostic des selles et de son emploi en diagnostic 
pr^coce de la fievre typhoide. Paris Thesis, 1903. 

de Freycinet. Prophylaxie de la fievre typhoide dans l'arm6e. Ann. 
d'Hygiene, 1891, xxv, 381. 

De Haen. Theses sistentes febrium divisiones. Vindob. 1760. 

Dehler. Zur Behandlung der Typhusbazillentrager. Munch, med. 
Woch., 1907, 779, 2134. 

Dehu, P. Etude sur le role du bacille d'Eberth dans les complications de 
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Delafield, F. and T. M. Prudden. A text-book of pathology. 7th Ed., 
1914, Wood and Co., N. Y. 

Delbet, P. L'or colloidal dans le traitement des infections chirurgicales. 
Soc. des Chirurgiens de Paris, 1916, Jan. 14. 

Dennemark. Die Griiber-Widalsche Reaktion bei klinischen Gesunden 
in der Umgebung Typhuskranker. Cent, f . Bakt., 1910, liv, 374. 

Deutsch, F. Zur Vakzinebehandlung des Typhus abdominalis. Wien. 
klin. Woch., 1915, No. 30, 810. 

Deve. Typhoide et paratyphoides. La Presse MSdicale, 1915, Nov., 
No. 53, 437. 

Ditthorn, F. and W. Schultz. Zur Antigenbehandlung des Typhus. 
Med. Klinik, 1915, xi, 100. 

Doerr, R. Experimentelle Untersuchungen tiber das Fortwuchern von 
Typhusbacillen in der Gallenblase. Cent. f. Bakt., 1905, xxxix, 624. 

Donaldson, R. and B. Clark. Agglutination reactions with Oxford 
standard agglutinable cultures. Lancet, 1916, ii, 546. 

Dopfer, W. Uber die Complicationen des lethalen Abdominaltyphus. 
Munch, med. Woch., 1888, xxxv, 620, 635. 

Dopter. Vaccination preventive contre la dysent^rie bacillaire. Ann . 
Inst. Past., 1909, xxiii, 677. 






BIBLIOGRAPHICAL INDEX 255 

Drechsfeld. Quoted by Ruhrah, q.v. 

Dreyer, G. Widal's reaction with sterilized cultures. Jour. Pathology 
and Bacteriology, 1909, xiii, 331. 

Dreyer, G. and A. C. Inman. Persistence of antibodies in blood of 
inoculated persons as estimated by agglutination tests. Lancet, 1915, 
II, No. 4796, 225. 

Dreyer, G., E. W. A. Walker and A. G. Gibson. The detection and 
identification of B. typhosus and B. paratyphosus.. Lancet, 1915, 
clxxxviii, 643. 

(2) Agglutination tests in inoculated persons and influence of 
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Apr. 8. 

(3) Typhoid and paratyphoid infection in relation to antityphoid 
inoculation. Lancet, 1915, clxxxviii, 324. 

Drigalski. Ueber Ergebnisse bei der Bekampfung des Typhus. Cent, f . 
Bakt., 1904, xxxv, 776. 

Drigalski and H. Conradi. Ueber ein Verfahren zum Nachweis der 
Typhusbacillen. Zeit. f. Hyg., 1902, xxxix, 283. 

Droba, St. Der Zusammenhang zwischen Typhusinfection und Chole. 
lithiasis auf Grund eines in der Klinik operirten Falles. Wien. klin- 
Woch., 1899, No. 46, 1141. 

Dublin, L. Typhoid fever and its sequelae. Am. Jour. Pub. Health, 

1915, v, 20. 
DuBois. The absorption of food in typhoid fever. Arch. Int. Med., 1912. 

x, 177. 
Durham, H. E. On a special action of the serum of highly immunized 

animals. Jour. Path, and Bact., 1897, iv, 13. 

Dziembrowski, S. V. Ein Malariarerezidiv nach Typhusschutzimpfung, 
Deut. med. Woch., 1915, xli, 1331. 

Ebeling, E. Ueber das Vorkommen von Typhusbacillen im Blut eines 
"gesunden" Bacillentragers. Berl. klin. Woch., 1914, 689. 

Eberth, C. J. Die Organismen in den Organen bei Typhus abdominalis. 
Virchows Archiv, 1880, lxxxi, 58. 

(2) Neue Untersuchungen iiber den Bacillus des Abdominal typhus. 
Virchows Archiv, 1881, lxxxiii, 486. 

Eggerth, H. See letter to Paltauf. Wien. klin. Woch., 1915, xxviii, 209. 

Eichhorst. Klinische Erfahrungen liber wiederholtes Erkranken an 
Abdominal typhus. Virchows Archiv, 1888, iii, 48. 

Elmeu, W. P. Study of a recent typhoid epidemic with especial reference 
to the use of antityphoid vaccines. Jour. Am. Med. Asso., 1915, 
lxiv, 1147. 



256 BIBLIOGRAPHICAL INDEX 

Elsxer. Untersuchungen liber electives Wachsthum der Bacterium 
coli-Arten und des Typhusbacillus und dessen diagnostische Ver- 
werthbarkeit. Zeit. f. Hyg., 1896, xxi, 25. 

Emmerich and Wagner. Typhusschutzimpfung und Infektion im 
Tierversuch. Medizin. Klinik, 1916, xii, 74. 

E.vdo, S. Ueber ein Verfahren zum Nachweis der Typhusbacillen. Cent, 
f. Bakt., 1904, xxxv, 109. 

Englander. Ueber intravenose Kochsalzinfusionen bei Typhus ab- 
dominalis. Wien. klin. Woch., 1915, xxviii, 1227. 

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1912. Springer, Berlin. 

Etienne, E. Similitude devolution de la fievre typhoide sur Taction de la 
serotherapie et de la vaccination. 

Faginolio, A. Nuove osservazioni e considerazioni sulla vaccinoterapia 
endovenosa nel tifo. Riforma med., 1916, xxxii, 365. 

Feistmantel, C. Uber Prophylaxie und Therapie des Typhus abdom- 
inahs mittels Impstoffen. Wien. klin. Woch., 1915, xxviii, 230. 

Fellner, B. Beitrag zur Therapie des Typhus abdominalis. Med. 

Klinik, 1915, xi, 1074. 
Fice^r, M. Typhus und Fhegen. Arch. f. Hyg., 1903, xlvi, 274. 

Findlay, J. W. and R. M. Buchanan. Case of typhoidal cholecystitis in 
which the usual symptoms of typhoid were absent, in which the 
Bacillus typhosus was isolated during life from the cystic and in- 
testinal contents. Glasgow Med. Jour., 1906, lxv, 177. 

Firth, R. H. A statistical study of anti-enteric inoculation. Jour. Royal 
Army Med. Corps, 1911, xvi, 589. 

Firth, R. H. and Horrock, W. H. An inquiry into the influence of soil, 
fabrics, and flies in the dissemination of enteric infection. Brit. Med. 
Jour., 1902, ii, 936. 

Flatten, H. Die Bekampfung der Einzelen ubertragbaren Krankheiten. 
Handb. der praktischen Hygiene. Abel. Fischer, 1913, 1, 634. 

Fleming, A. Typhoid inoculation in the forces. The Practitioner, 1916, 

Jan., xcvi, 85. 
Fletcher, J. P. A rational indication for bacterial vaccine in typhoid 

fever. Jour. Am. Med. Asso., 1911, Apr. 15. 

Flexner, S. Unusual forms of infection with the typhoid bacillus, with 
especial reference to typhoid fever without intestinal lesions. Johns 
Hopkins Hosp. Rep., 1900, viii. 

Flint, A. Clinical reports on continued fever. G. H. Derby & Co. 
Buffalo, 1852. 



BIBLIOGRAPHICAL INDEX 257 

Floyd, C. and Barker, W. W. The typhoid cutaneous reaction. Am. 
Jour. Med. Sci., 1909, cxxxviii, 188. 

Fogh, R. Ein Fall von posttyphosen supperativen Knockentzundung 
mit auserordentlich langwierigen Verlaufe. Deut. med. Woch., 
1908, xxxiv, 1305. 

Force, J. N. Institutional vaccination against typhoid fever. Am. Jour. 
Pub. Health, 1913, III, 750. 

(2) University of California Bull., ix, No. 6. Annual report of the 
President of the University, 1914-15, p. 112. 

Force, J. N. and I. M. Stevens. Further studies on typhoidin. Arch. 
Int. Med., 1917, xix, 440. 

Fornet, W. Ein Beitrag zur Ziichtung von Typhusbazillen aus dem 
Blut. Munch, med. Woch., 1906, 1053. 

(2) Immunitat bei Typhus. Kolle & Wassermann, 1912, III, 837, 
Handbuch der path. Mikroorgan. 

(3) Die Pracipitatsreaktion. Munch, med. Woch., 1906, No. 38. 

(4) Statistisches liber den Typhus and die Typhusbekampfung im 
Sudwesten des Reichs. Arb. kais. Ges., 1912, xli, 448. 

Fornet, W. and Muller. Zur Herstellung und Verwendung prazip- 
itierender Sera, insbesondere fur den Nachweis von Pferdefleisch. 
Zeitschr. f. biol. Techn. u. Meth., 1908, I, 201. 

Forster, J. Ueber die Beziehungen des Typhus und Paratyphus zu 
dem Gallewegen. Munch, med. Woch., 1908, No. 1, 288. 

Forster, S. and H. Kayser. Ueber das Vorkommen von Typhusbacillen 
in der Galle von Typhuskranken und Typhusbacillentragern. Munch, 
med. Woch., No. 31, 147. 

Foster. Statement in British House of Commons. Jour. Am. Med. 
Asso., London Letter, 1916, Nov. 18, 1537. 

Fraenkel, E. Ueber spezifische Behandlung des Abdominaltyphus. 
Deut. med. Woch., 1893, xix, 985. 

Fraenkel, E. and P. Kraus. Bakteriologisches und Experimentelles 
liber die Galle. Zt. f. Hyg., 1899, xxxii, 97. 

Fraenkel, E. and M. Simmonds. Die aetologische Bedeutung des 
Typhusbazillus. Voss. Hamburg and Leipzig, 1886. 

(2) Zur Aetiologie des Abdominaltyphus. Cent. f. klin. Med., 

1885, vi, 737. 

(3) Weitere Untersuchungen iiber die Aetiologie des Abdominal- 
typhus. Zt. f. Hyg., 1887, ii, 138. 

Friedberger, E. Zur Geschichte der Typhusschutzimpfung des Men- 
schen. Cent. f. Bakt., 1907, xliv, 560. 

(2) Die Methoden der Schutzimpfung gegen Typhus usw. Kraus 
and Levaditi Handbuch, 1908, i, 722. 



258 BIBLIOGRAPHICAL INDEX 

Friedberger, E. and S. Mita. Ueber Anaphylaxis Ztsch. f. Immuni- 
tatsfor., 1911, x, 216. 

Friedberger, E. and C. Moreschi. Vergleichende Untersuchungen 
iiber die aktive lmmunisierung von Kaninchen gegen Cholera und 
Typhus. Deut. med. Woch., 1906, No. 49. 

Frosch, P. Festschrift zur 60 Geburtstage von R. Koch, 1903, 691. 
Fischer, Jena. 

(2) Die Verbreitung des Typhus durch sogenannte "Daueraus- 
scheider und Bacillentrager." Klin. Jahrb., 1907, xix, 507. 

Frugoni, C. Appunti pratici intorno al tifo di guerra. Policlinico, 
Rome, 1916, xxiii, 229. 

Fulton, J. S. Typhoid fever; some unconsidered hindrances in its 
prophylaxis. Jour. Am. Med. Asso., 1904, p. 73. 

von Futterer, A. Untersuchungen liber den Typhus abdominalis. 
Munch, med. Woch., 1888, No. 19, 315. 

Gaehtgens, W. Ueber die Erhohung der Leistungsfahigkeit des En- 
doschen Fuchsinagars durch den Zusatz von Koffein. Cent. f. Bakt., 
1905, xxxix, 634. 

Gaethgens, W. and G. Bruckner. Vergleichende Untersuchungen 
iiber einige neurere Typhusnahrboden und Erfahrungen iiber den 
Wert der Agglutination, Blutkultur und Stuhlziichtung fur die 
Diagnose des Abdominaltyphus. Cent. f. Bakt., 1909, liii, 559. 

Gaethgens, W. and W. Kamm. Welchen Wert hat die "Fadenreaktion" 
fur die Diagnose des Abdominaltyphus fiir das Auffinden von Typhus- 
bazillentragern und die Differenzierung von Bakterien der Para- 
typhusgruppe. Munch, med. Woch., 1910, No. 26, 1389. 

Gaffy. Zur Aetiologie des Abdominaltyphus. Mitt. a. d. kais. Gesund- 
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Gaither, J. G. Antityphoid inoculation. Correspondence, Jour. Am. 
Med. Asso., 1914, lxiii, 1314. 

Galambos, A. Die Behandlung des Typhus abdominalis, Paratyphus A 
und B mit der Besredkaschen Vakzine. Zt. f. klin. Med., 1916, 
lxxxiii, 127. 

Garbat, A. L. Studies in typhoid fever. Jour. Am. Med. Asso., 1916, 
lxvii, 149. 

(2) Duodenal cultures in typhoid fever as a means of determining 
complete convalescence. Jour. Am. Med. Asso., 1916, lxvii, 
1493. 

(3) Sensitized versus non-sensitized typhoid bacteria in the prophy- 
laxis and treatment of typhoid fever. Jour. Am. Med. Asso., 
1915, lxiv, 489. 



BIBLIOGRAPHICAL INDEX 259 

Garbat, A. L. and F. Meyeh. Ueber Typhus-Heilserum. Zt. f. ex- 
perimentelle Path., 1910, viii, 1. 

Gartner. Ueber die Fleischvergiftung in Frankenhausen am Kyffhauser 
und den Erreger derselben. Correspondenzbl. des Allg. arztl. Vereins 
von Thiiringen, 1888, No. 9. 

Gaupp, 0. Erfahrungen mit Krauschem Typhusserum. Beit, zur 
Klinik der Infektion und Immunitatsforschung. 1914, ii, 131. 

Gat. Un traitement pratique de la fievre typhoiide aux armies. La 
Presse Medicale, 1915, Mar. 4, 67. 

Gay, F. P. Vaccination and serum therapy against the bacillus of dys- 
entery. Univ. of Penn. Med. Bull., 1902, xv, 307. 

(2) Abortive treatment of typhoid fever by sensitized vaccine 

sediment. Jour. Am. Med. Asso., 1915, lxv, 322. 

(3) Further experience in the treatment of typhoid fever by the 
intravenous injection of sensitized typhoid vaccine sediment. 
Jour. Lab. and Clin. Med., 1917, ii, 785. 

Gay, F. P. and H. T. Chickering. Treatment of typhoid fever by in- 
travenous injections of polyvalent sensitized typhoid vaccine sed- 
iment. Archives of Inter. Med., 1916, xvii, 303. 

Gay, F. P. and E. Claypole. The typhoid carrier state in rabbits as a 
method of determining the comparative immunizing value of prep- 
arations of the typhoid bacillus. Studies in typhoid immunization I. 
Arch. Inter. Med., 1913, xii, 613. 

(2) Agglutinability of blood and agar strains of the typhoid bacillus. 

Studies in typhoid immunization II. Arch. Inter. Med., 1913, 
xii, 622. 

(3) Experimental study of methods of prophylactic immunization 
against typhoid fever. Studies in typhoid immunization V. 
Arch. Inter. Med., 1914, xiv, 671. 

(4) Specific hyperleucocytosis. Studies in typhoid immunization 
IV. Arch. Inter. Med., 1914, xiv, 671. 

Gay, F. P. and J. G. Fitzgerald. An improved rapid method of pro- 
ducing precipitins and hemolysins. Univ. of Calif. Pub. in Path., 
1912, ii, No. 8. 

Gay, F. P. and J. N. Force. A skin reaction indicative of immunity 
against typhoid fever. Studies in typhoid immunization III. Arch. 
Inter. Med., 1914, xiii, 471. 

Gay, F. P. and A. R. Lamb. The application of the typhoidin test in a 
group of nurses and physicians. Jour. Lab. and Clin. Med., 1917, 
ii, 217. 

Gay, F. P. and W. P. Lucas. The value of the conglutination reaction as 
a means of diagnosis of acute bacterial infection. Proc. Soc. Exper. 
Biol, and Med., 1909, vii, 21. 



260 BIBLIOGRAPHICAL INDEX 

Gendron. Dothienenterite observee aux environs de Chateau de Loir. 
Arch. gen. de M6d., 1834, xviii, Ser. 1. 

Gerard, P. and Fenestre. Case of paratyphoid A plus typhoid. Prog- 
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Apr. 28.) 

Gerhard, W. W. On the typhoid fever which occurred in Philadelphia 
in the spring and summer of 1836. Am. Jour. Med. Sci., 1837, xix, 
289. 

Gilbert, A. and L. Fournier. Lithiase biliaire experimentale. Compt. 
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Gilbert, A. and J. Girode. Contribution a l'6tude bacteriologique des 
voies biliares. Semaine med., 1890, x, 481. 

(2) Des angiocholite infectieuses ascendantes suppuratives. 
Compt. rend. Soc. bid., 1891, xliii, 217. 

Gilchrist. Essay on nervous fevers. Edinb. Med. Essays and Observa- 
tions, 1734, iv. 

Giroux. Complications gemtales des affections paratyphoides. Presse 
MeU, 1915, No. 42, Sept. 9. 

Glenard. Traits de la fievre typhoide a Lyon. Gazz. Hebd. M£d. et 
Chir., Paris, 1883. 

Glinchikoff, V. I. Changes in the leucocytes under the influence of re- 
peated injections of antityphoid vaccine. Russky Vrach, 1916, xv, 
726. (Jour. Am. Med. Asso., 1916). 

Goebel. Bericht iiber das Sektionsergebnis bei zwei chronischen 
Typhusbazillentragern. Zeit. f. Hyg., 1914, lxxviii, 555. 

Goldscheider. Impfmilzschwellung und Typhusdiagnose. Deut. med. 
Woch., 1915, xli, 1177. 

Goldscheider and Aust. Uber die spezifische Behandlung des Typhus 
abdominalis mit abgetoteten Kulturen von Typhusbazillen. Deut. 
med. Woch., 1915, xli, 361. 

Goldscheider and Kroner. Ueber den Einfluss der Typhusschutzimp- 
fungen aud die Typhuserkrankungen bei der Armee im Herbst und 
Winter, 1914-15. Berl. klin. Woch., 1915, hi, 933, 968, 1001. 

Graham. Death rate in acute infections. Jour. Am. Med. Asso., 1916, 
lxvii, 1272. 

Gregg, D. A typhoid carrier 52 years after recovery. Boston Med. 
& Surg. Jour., 1908, cliv, 80. 

Grenet, H. and L. Fortineau. Etude de quelques cas de fievre para- 
typhoide. Reunion Meclico-Chirurgicale de l'Armee, Jan. 14, 1916. 
Presse Medicale, 1916, No. 6, 68. 



BIBLIOGRAPHICAL INDEX 261 

(2) Etude sur un epidemie d'infection typhoidique. Soc. M6d. des 
Hopitaux, 1915, Dec. 24. 

Geimme. Ein unter dem Bilde der Weilschen Krankheit verlaufender 

Fall von Typhus abdominalis, entstanden durch Autoinfektion von 

der Gallenblase her. Munch, med. Woch., 1907, liv, 1822. 

(2) Ueber die Typhusbazillentrager in den Irrenanstalten. Munch, 
med. Woch., 1908, lv, No. 1. 
Grobl and Hever. Ueber die Immunkorperbildung bei Impfungen mit 

verschieden Typhusimpfstoffen. Wien. klin. Woch., 1915, xxviii, 

1383. 
Groer, F. v. Zur Frage der aogenannten Vaccine oder Bakteriotherapie: 

Ergotrope Therapie des Typhus abdominalis. Munch, med. Woch., 

1915, lxii, 1312. 
Gruber, M. and H. E. Durham. Eine neue Methode zur raschen 

Erkennung des Cholera Vibrio und des Typhusbacillen. Munch. 

med. Woch., 1896, No. 13, 285. 

Grunbaum, A. S. Some experiments on enteric, scarlet fever and measles 
in the chimpanzee. Brit. Med. Jour., 1904, Apr. 9, 817. 

(2) Blood in the identification of bacterial species. Science Prog., 
1897. 
Guinon, L. and Malarte. Quelques cas de bacteriotherapie anti- 
typhique chez Penfant. Bull. Soc. de P6diatrie, 1914, xvi, 1. 

Gwyn, N. On infection with a para-colon bacillus in a case with all the 
clinical features of typhoid fever. Johns Hopkins Hosp. Bull., 1898, 
ix, 54. 

Haendel und Baerthlein. Ueber chininfeste Bakterienstamme. Cent, 
f. Bakt., 1913, Ref., lvii, Beiheft, 196. 

Hage and Korff-Petersen. Typhusschutzimpfung und Typhus- 
diagnose. Deut. med. Woch., 1915, xli, 1328. 

Hahn, M. Immunisierung und Heilversuche mit plasmatischen Zell- 
saften von Bakterien. Munch, med. Woch., 1897, xliv, 1347. 

Haibe, A. A propos des infections de laboratoire a bacilles typhiques. 
Compt. rend. Soc. Biol., 1913, lxxiv, 998. 

Hailer, E. and W. Rimpau. Versuche uber Abtotung von Typhus- 

bazillen im Organism us. Arbeit, aus kais. Gesundheitsamte, 1911 

xxxvi, 409. 
Hall, H. C. Untersuchungen uber die Bedeutung des Petrolaethers fur 

den Nachweis von Typhus und Paratyphusbakterien im Stuhl. 

Berl. klin. Woch., 1915, Dec. 27, No. 52. 

Hamilton, A. The fly as a carrier of typhoid; an inquiry into the part 
played by the common house fly in the recent epidemic of typhoid, 
fever in Chicago. Jour. Am. Med. Asso., 1903, xl, 576. 



262 BIBLIOGRAPHICAL INDEX 

Hare and Beardsley. Medical complications, accidents and sequels of 
typhoid. Lea and Febiger, Phila., 1909. 

Harrison, W. S. Memorandum regarding antityphoid inoculation. Jour. 
Roy. Army Med. Corps, 1906, vii, 63. 

Hartsock, Frederick M. Antityphoid vaccination. Jour. Am. Med. 
Asso., 1910, liv, 2123. 

Hatchel, F. W. and H. W. Stoner. Inoculation against typhoid. Jour. 
Am. Med. Asso., 1912, liv, 1364. 

(2) Inoculations against typhoid in Maryland. Am. Jour. Pub. 
Health, 1916, vi, 703. 

Herz, A. Die Behandlung der Bazillentrager. Wien. klin. Woch., 1916, 
1290, Oct. 11. 

Hess, A. The use of a simple duodenal catheter in the diagnosis and 
treatment of certain cases of vomiting in children. Am. Jour. Dis- 
eases of Children, 1912, 133, March. 

Hildenbrand. Ueber den ansteckenden Typhus. Wien, 1810. 

Hilgerman, R. Ueber Bazillentrager beim Typhus. Klin. Jahrb., 1908, 

xix, H 3. 
Hirsch, C. Atypische Verlaufsformen des Typhus im Felde. Berl. klin. 
Woch., 1915, lii, No. 30. 

(2) Ueber atypische Verlaufsformen des Typhus im Felde. Wien. 
klin. Woch., 1915, xxviii, 955. 

Hiss, Philip H. On a method of isolating and identifying Bacillus ty- 
phosus based on a study of Bacillus typhosus and members of the 
colon group in semi-solid culture media. Jour. Exper. Med., 1897, 
vii, 677. 

(2) Studies in the bacteriology of typhoid fever, etc. Med. News, 
1901, May 11. 
Hoffmann. Opera omnia physico-medica. 1699. Ed. Schultze, Gen- 
evae, 1740. 

Hohlweg. Ueber den Einfluss der Typhusschutzimpfung auf den Nach- 
weis der Typhusbazillen in kreisenden Blut. Munch, med. Woch., 
1915, lxii, No. 16. 

Holler, G. Zur Vakzinetherapie des Typhus abdominalis. Zt. f. klin. 
Med., 1915, lxxxi, 462. 

(2) Erfahrungen iiber Bakteriotherapie des Typhus abdominalis. 
Med. Klinik, 1915, xi, 639 and 668. 

Holscher. Ueber die Complicationen bei 2000 Fallen von lethalen 
Abdominaltyphus. Munch, med. Woch., 1891, xliii, 43. 

Holt-Harris, J. E. and 0. Teague. A new culture medium for the 
isolation of Bacillus typhosus from stools. Jour. Infec. Dis., 1916, 
xviii, 596. 



BIBLIOGRAPHICAL INDEX 263 

Homolle. Quoted by J. Minet, q.v. 

Hooker, Sanford B. A comparison of the antigenic properties of dif- 
ferent strains of Bacillus typhosus. Jour. Immunology, 1916, ii, 1. 

Howell, K. Observations on the production of antibodies after anti- 
typhoid inoculation. Jour. Infec. Dis., 1916, xix, 63. 

Hueppe, F. In remarks on articles by Fodor and Wyssokowitch. Fort- 
schr. d. Med., 1886, iv, 447. 

(2) Schutzimpfung bei Typhus and Cholera. Berl. klin. Woch., 
1915, lii, 1274. 

Hunter, W. Roy. Coll. Surg. Path. Catalogue. (See Murchison *)• 

Huxham. Essay on fevers. London, 1739. 

Ichikawa, S. Abortivbehandlung von typhosen Krankheiten. Mitteil. d. 
medic. Gesellsch. zu. Tokio, 1914, xxviii, H. 21. 

Ickert, F. Der Einfluss der Typhusschutzimpfung auf der weisse 
Blutbild. Beitrage z. klin., Infekkrank. und Immunitatsf., 1915, 
iv, 153. 

Irwin, T. and T. H. Houston. On a typhoid carrier treated successfully 
by the inoculation of typhoid vaccine. Lancet, 1909, No. 5. 

Jacobsen, K. A. Untersuchungen liber die Lebensfahigkeit der Cholera- 
vibrionen im Meerwasser. Cent. f. Bakt., 1910, lvi, 201. 

Jaffe, R. H. Die Wirkung des Petrolathers auf die Bakterien der 
Typhus-Koligruppe. Wien. klin. Woch., 1915, xxviii, 418. 

Jeanneret, L. Skin typhine tests and skin diphtherine tests for typhoid 
and for diphtheria in young children. Revue Med. de la Suisse 
Romande, 1916, xxxvi, No. 10. (Jour. Am. Med. Asso., 1916, 1881.) 

Jenner, Wm. On the identity or non-identity of the specific cause of 
typhoid, typhus and relapsing fever. Med. Chirur. Trans., xxxiii. 

(2) Typhus and typhoid: an attempt to determine the question of 
their identity or non-identity by an analysis of their symptoms 
and post-mortem appearances. Edin. Month. Jour. Med. 
Sci., ix, x, 1849, 1850. 

(3) Fevers and diphtheria. Macmillan & Co., N. Y., 1893. 

Jez, V. Ueber Typhusbehandlung (Abdominaltyphus) mit einen Anti- 
typhus Extract. Wien. med. Woch., 1899, 346. 

Jobling and Petersen. Bacteriotherapy in typhoid fever. Jour. Am. 
Med. Asso., 1915, lxv, 515- 

Jochmann, G. Lehrbuch der Infektionskrankheiten. Springer, Berlin, 
1914. 

JoETrEV, K. W. Typhusbekamofung im Felde durch ein einfaches 
Verfahren zur Handedisinfection. Deut. med. Woch., 1915, xli, 1388. 



264 BIBLIOGRAPHICAL INDEX 

Johan, B. Ueber eine Typhusvakzine mit milderer Reaktion. Deut. 
med. Woch., 1915, xli, 826. 

Johnson, I. P. and A. I. Milne. Combined preventive inoculation 
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Johnston. A research on the experimental typhoid carrier state in the 
rabbit. Jour. Med. Res., 1912, xxvii, 177. 

Josias, A. S6roth6rapie de la fievre typhoiide. Bull, de l'Acad. de m6d. 
1906, lv, 301. 

Josu£, 0. and Belloir, F. Autovaccination antityphique. Cent. f. 
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Kabeshima. Ueber Typhus und Paratyphusschutzimpfung mittels 
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Schutzimpfung in der kaiserlichen Japanisschen Marine. Cent. f. 
Bakt., 1914, lxxiv, 294. 

Kalberlan, F. Die Behandlung der Typhusbazillentrager. Med. 
Klinik, 1915, xi, 581. 

Kammerer, H. and R. W. Woltering. Typhusschutzimpfung und 
Milzschwellung. Miinch. med. Woch., 1916, lxiii, 57. 

Karaffa-Korboutt. Contribution a l'dtude du se"rum des chevaux 
immunises avec le vaccin antityphique de Besredka. Compt. rend. 
Soc. de Biol., 1914, lxxvi, 279. 

Karell, W. and T. Lttcksch. Die Befreiung der Bacillenausscheidern 
von ihrem Uebel durch Behandlung mit homologen Impfstoffe. Wien. 
klin. Woch., 1916, xxix, No. 7. 

Kaspar, F. Zur Autoreinfektion des Typhusbacillenwirtes. Mitteil- 
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Kast, L. and C. Guiig. Ueber Hypoleucozytose beim Abdominaltyphus 
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Kayser, Heinrich. Uber Untersuchungen bei Personen die vor Jahren 
Typhus durchgemacht haben, und die Gefahrlichkeit von " Bazillen- 
tragern." Arbeiten a. d. kais. Gesungheitsamte, 1907, xxv, 223. 
(2) Ueber die Art der Typhusausbreitung in einer Stadt. Mtinch. 
med. Woch., 1909, lvi, 1067, 1130. 

Keen, W. W. Surgical complications and sequels of typhoid fever. 
Phila., 1898, W. B. Saunders & Co. 

Kelly, F. L. Personal communication. 

Kendall, A. I. Bacteriology, general, pathological and intestinal. Lea 
and Febiger, Phila., 1916. 



BIBLIOGRAPHICAL INDEX 265 

Kilgore, E. S. The typhoidin quotient. Arch. Inter. Med., 1916, xvii, 25. 
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Kiralyfi, G. Die bakteriologische und chemische Untersuchung der 
Galle "in vivo" bei Typhus abdominalis. Berl. klin. Woch., 1912, 
1985. 

Kisskalt, K. Laboratoriumsinfektionen mit Typhusbazillen. Zt. f. 
Hyg., 1915, lxxx, 145. 

(2) Ein Modifikation des Typhusimpfstoffes. Deut. med. Woch., 
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Kitasato, S. Quoted by Lescohier, q.v. 

Klebs. Der Ileotyphus eine Schistomycose. Arch. f. exp. Path, u 
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(2) Der Bacillus der Abdominaltyphus und der typhose Process. 
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(3) Die allgemeine Pathologic Fischer, 1887, Part I. 

Klein, E. Flies as carriers of the Bacillus typhosus. Brit. Med. Jour., 
1908, ii, 1150. 

Klein, H. The opsonins in typhoid immunity. Johns Hopkins Bull., 
1907, xviii, 245. 

Klieneberger, C. Agglutinationstiter bei Infektionskrankheiten im 
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Klinger, P. Uber Typhusbacillentrager. Arb. a. d. kais. Ges., 1906. 
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(2) Epidemiologische Beobachtungen bei der Typhusbekampfung 
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Kober, G. M. The general movement of typhoid fever and tuberculosis 
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Koch, J. Typhusbacillen und Gallenblase. Zt. f. Hyg., 1909, Ixii, 1. 

Koch, R. Zur Untersuchung von pathogenen Organismen. Mitt. a. d. 
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(2) Die Bekampfung des Typhus. Vortrag gehalten in der Sitzung 
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Koenigsfeld, H. Eine neue einfache Methode zum beschleunigten 
Typhusbazillennachweis in kleinen Mengen Blut. Munch, med. 
Woch., 1915, 130. 

(2) Ein neues Prinzip der Serumtherapie bei Infektionskrankheiten, 
mit besondere Beriichtsichtigung des Typhus abdominalis. 
Munch, med. Woch., 1915, No. 8, 253. 



266 BIBLIOGRAPHICAL INDEX 

Kolle, W. and H. Hetsch. Die experimentelle Bakteriologie und die 
Infektionskrankheiten. V. I, p. 261, III Auf., 1911, Urban and 
Schwartzberg, Berlin. 

Konjajeff. Die bakterielle Erkrankung der Niere beim Abdominal- 
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Koranyi, A. V. Zur Vakzinebehandlung des Typhus abdominalis. 
Wien. klin. Woch., 1915, xxviii, 85. 

Korczynski, L. von. Paratyphose Erkrankungen. Medizin. Klinik, 
Berlin, 1916, xii, No. 3. 

Kossel, H. Ueber Typhusschutzimpfung. Berl. klin. Woch., 1914, 1857. 

Kramer, S. P. The pathogenesis of gallstones. Jour. Exp. Med., 1907, 
ix, 319. 

Kraus, R. Bemerkungen iiber Schutzimpfung und einer Bakteriotherapie 
des Typhus abdominalis. Wien. klin. Woch., 1914, xxvii, 1443. 
(2) Ueber Bakteriotherapie akuter Infektionskrankheiten. Wien. 
klin. Woch., 1915, 29. 

Kraus and Mazza. Zur Frage der Vakzinetherapie des Typhus abdom- 
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Kraus, R. and R. v. Stenttzer. Uber Gifte des Typhusbazillen und 
fiber Gift neutralizierende Eigenschaften des Immuneserums. Zt. f. 
Immunitatsforsch., 1909, hi, 646. 

Krumbhaar and Richardson. The value of typhoid vaccine in the 
treatment of typhoid fever. Am. Jour. Med. Sci., 1915, cxlix, 406. 

Krumwiede, C. Fecal examinations of a regiment infected with Bacillus 
paratyphosus A, with special reference to normal carriers. Jour. 
Infec. Dis., 1917, xxi, 141. 

Krumwiede, C, J. Pratt and L. Kohn. Studies on the paratyphoid 
enteriditis group. I. Jour. Med. Res., 1916, xxxiv, 355. 

Kuhn, P. Weitere Beobachtung fiber die Ergebnisse des Typhusschutz- 
impfung in der Schutztruppe ffir Sfidwestafrika. Deut. Militarartz 
Woch., 1907, xxxvi. 

Kuhnemann, G. Ueber Kapselbildung beim Typhusbacillus. Cent. f. 
Bakt., 1911, Ivii, 497. 

Kutscher, K. H. Abdominaltyphus. Kolle and Wassermann: Hand- 
buch der pathogenen Mikroorganismen. II Auflage. Fischer, Jena, 
1913, hi, 717. 

Kutscher and E. Meinicke. Vergleichende Untersuchungen fiber 
Paratyphus-, Enteritis- und Mausetyphusbakterien und ihre im- 
munisatorischen Beziehungen. Zt. f. Hyg., 1906, lii, 301. 



BIBLIOGRAPHICAL INDEX 267 

Labb£, M. Les infections typholdes et paratyphoides chez les vaccines. 
Ann. de MeU, 1916, iii, 13. 

(2) Vaccination et paratyphoides. Presse M6d., 1916, No. 3, 20. 

(3) Les fievres paratyphoides. Paris M6d., 1915, v, 212. 

Labbe, M. and Moussaud. Traitement de la fievre typhoide par Tor 
colloidal. Presse Med., 1916, No. 14, 105. 

Labor, M. Zu den zytologischen Veranderungen der Typhusimpfung. 
Wien. klin. Woch., 1916, xxix, 1393. 

Lampe, R. Ein Beitrag zum Verlauf des Typhus bei Geimpften. Deut. 
med. Woch., 1916, 1120. 

Lamy, M. Fievre typhoide et lithiase biliare. Paris Thesis, 1909. 

Lancisi. Opera omnia. Genevae, 1718, Lib. 1. 

Landmann, G. Ueber eine neue Methode der bakteriologischen Typhus- 
diagnose. Arb. an der Stadt Krankenhaus, Frankfurt, 1896, 243. 

Landouzy, L. Note sur 600 injections antityphoidiques. Bull. Acad, de 

MeU, 1915, lxxiv, 79. 

(2) Fievre typhoide et fi&vres paratyphoides, etc. Presse M6d., 
1914, No. 78, 707. 
Landsberger, O. Zur Prognosestellung bei Typhus abdominalis. Med. 

Klinik, 1915, xi, 1078. 
Langer, R. Untersuchung iiber einen mit Knotchenbildung einher- 

gehenden Prozess in der Leber des Kalbes und dessen Erreger. Diss., 

Giessen, 1904. 
Langrish. Modern Theory and Practice of Physic. London, 1735. 

Leboeuf, A. and P. Braun. Notes sur la technique de I'hemoculture au 
cours des 6tats typholdes. L'hemoculture dans l'urine. Comp. 
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Leclainche, E. Sur la s^rotherapie du rouget du pore. Comp. Rend. 
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Ledingham, J. C. G. and J. A. Arkwright. The carrier problem in 
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Leger, Abt and Dumont. Documents relatifs aux infections typhiques 
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Leishmann, W. B. Preliminary note on antityphoid vaccine in the treat- 
ment of enteric fever. Jour. Roy. Army Corps, 1909, xii, 136. 

Lemierre, A. and P. Abrami. Cholecystites et pericholecystites hem- 
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Lentz, O. Ueber chronische Typhusbazillentrager. Klin. Jahrb., 1905, 
xiv, 475. 

(2) tiber den Fornetschen Typhusimpfstoff. Hygien. Rund., 1915, 
xxv, 891. 



268 BIBLIOGRAPHICAL INDEX 

Lentz, 0. and J. Tietz. Eine Anrechnungsmethode fiir Typhus und 
Paratyphusbacillen. Munch, med. Woch., 1903, No. 49. 

Lescohier, A. W. Duration of Immunity following small-pox vaccina- 
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Letulle, M. Des pyrexies abortives. Paris, Asselm and Herizean, 1886. 

Letulle, M. and Mage. Traitement de la fievre typhoide par Tor colloi- 
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Leuchs. Ueber Malachitgrunnahrboden zum Nachweis von Typhus- 
und Paratyphusbacillen. Deut. med. Woch., 1906, 1330. 

Leuret. Memoire sur la dothienenterite a Nancy. Arch. gen. de M6d., 
1828, xviii, Ser. 1. 

Levy, E. and E. Bruch. Vergleichende experimentelle Untersuchungen 
zwischen drei Typhusvakzinen, die sowohl Bakterienleibersubstanzen 
als auch losliche Stoffwechselprodukte enthalten. Arb. a. d. kais. 
Gesundh., 1913, xliv, 150. 

Levy, E. and W. Gaethgens. Ueber die Verbreitung der Typhusbacillen 
in den Lymphdriisen bei Typhusleichen. Arb. a. d. kais. Ges.-Amte, 
1908, xxviii, 295. 

Levy, E. and H. Kayser. Ueber die Lebensdauer von Typhusbacillen 
die im Stuhl entleert wurden. Cent. f. Bakt., 1902, xxxiii, 489. 
(2) Bakteriologische Befund bei der Autopsie eines Bacillentragers. 
Miinch. med. Woch., 1906, No. 50, 2434. 

Levy, E. and P. Levy. Ueber das Hamolysin des Typhusbacillus. Cent, 
f. Bakt., 1901, xxx, 405. 

Levy, P. and P. Vallery-Radot. Differentiation pratique du bacille 
d'Eberth, du paratyphique A, du paratyphique B par un seul milieu: 
le g61o-gluco-plomb. Presse M6d., 1915, No. 51, 420. 

Leydhecker, E. Ueber das Verhalten der weissen Blutkorperchen bei 
Typhusbacillentragern. Diss., Strassburg, 1910. 

Liebermann, L. v. Vakzinebehandlung der Typhuskranken. Deut. 
med. Woch... 1915, xli, 937. 

Liebermann, L. v. and D. Acel. Neuer gefarbter Nahrboden zur 
scharfen Unterscheidung saurebildender Bakterien von anderen, in 
besondere der Colibazillus von Typhusbazillus. Deut. med. Woch., 
1914, 2093. 

(2) Uber Antigenewirkung sensibilisierter und nicht sensibilisierter 
Blutzellen und Typhusbacillen. Deut. med. Woch., 1915, 
xli, 965. 

Liebermeister, C. v. Einleitung zu den Infektionskrankheiten und Ty- 
phus abdominalis. v. Ziemssen's Handbuch der speciellen Pathologie 
und Therapie, ii, 82, 155. 



BIBLIOGRAPHICAL INDEX 269 

Liefmann. Beitrag zur Behandlung der Typhusbazillentrager. Munch, 
med. Woch., 1909, No. 10. 

Lignteres. Contribution a l'^tude de septicemic hemorrhagique. 
Buenos Ayres, 1900. 

Link, R. Ueber Hautreaktionen bei Impfungen mit abgetbteten Typhus- 
Paratyphus B und Colikulturen. Mtinch. med. Woch., 1908, lv, 730. 

Lipp, H. Das Blutbild bei Typhus- und Choleraschutzimpfung. Munch, 
med. Woch, 1915, lxii, 539. 

Loeffler, F. tlber ein neues Verfahren zur Gewinnung von Antikorpern. 
Deut. med. Woch., 1904, xxii, 113. 

(2) Ueber Epidemieen unter den im hygienischen Institute zu 
Griefswald gehaltenen Mausen und iiber die Bekampfung der 
Feldmausplage. Cent. f. Bakt., 1892, xi, 129. 

Lombard. Observations suggested by a comparison of the post-mortem 
appearances of typhus fever in Dublin, Paris and Geneva. Dublin 
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Longcope, W. T. A study of the bone-marrow in typhoid fever and other 
acute infections. Bull, of the Ayer Clin. Lab., 1905, No. 2, 1. 

(2) Personal communication. 

(3) Paracolon infection together with the report of a fatal case 
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Louis, P. C. A. Recherches anatomiques, pathologiques et therapeu- 
tiques sur la maladie connue sous les noms de fievre typholde, etc. 
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Louis and Combe. Indication et technique de la vaccination antity- 
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d'Hyg. et de Pol. saint., 1912, xxxiv, 1325. 

Lowr, J. Zur Symptomatologie der Typhusschutzimpfung. Med. 
Klinik, 1915, No. 26, 728. 

Lowt, R., F. Lucksch and E. Wilhelm. Zur Vaccinatherapie des 
Typhus abdominalis. Wien. klin. Woch., 1915, xxviii, 756. 

Lucksch, F. Die Heterovakzinebehandlung des Typhus abdominalis. 
Wien. klin. Woch., 1915, xxviii, 707. 

Ludke, H. Ueber den latenten Mikrobisums der Typhusbazillen. 
Munch, med. Woch., 1909, lvi, 57. 

(2) Ueber die Gewinnung und Wirkung von Typhusheilserum. 

Deut. Archiv. f. klin. Med., 1910, xcviii, 395. 

(3) Behandlung des Abdominaltyphus mit intra venosen Injek- 

tionen von Albumosen. Munch, med. Woch., 1915, 321. 

Lyster, W. Vaccination against typhoid in the United States army. 
Jour. Am. Med. Asso., 1915, lxv, 510. 



270 BIBLIOGRAPHICAL INDEX 

MacBride. Introduction to theory and practice of physic. London, 
1772. 

MacFadyean, A. and S. Rowland. Upon the intracellular constituents 
of the typhoid bacillus. Cent. f. Bakt., 1903, xxxiv, 765. 

Magendie, F. Quelques experiences sur les effets des substances en 
putrefaction. Jour, de Physiol., iii, 1823. 

Mallory, F. B. A histological study of typhoid fever. Jour. Exper. 
Med., 1898, iii, 611. 

Mandelbaum, M. Ueber das Bacterium metatyphi. Cent. f. Bakt., 
1912, lxiii, 46. 

(2) Eine neue einfache Methode zur Typhusdiagnose. Munch, 
med. Woch., 1910, H. 4, 178. 

Mann, B. L., F. Rainsford and M. Warren. Report of blood cultures 
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Marie, A. Immunisation par des melanges de virus rabique et de s6rum 
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Marrassini, A. Ueber das Vorhandsein einer den Korper einiger Bak- 
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Martin, S. Intracellular constituents of the typhoid bacillus. Brit. Med. 
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Marx. Die experimentelle Diagnostik, Serumtherapie und Prophylaxe 
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Matthes, M. Versuche zur Immunisierung gegen Typhus; nach Ver- 
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Maurange, M. G. Statistique de 39,215 injections antityphoidiques et 
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Maverick, A. Typhoid vaccination and the Widal reaction. N. Y. 
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Mayer, G. Ueber Typhus, Paratyphus und deren Bekampfung. Cent. 
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(2) Zur Vakzinetherapie des Typhus abdominalis bei den prophy- 
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Mazza, S. Die Bakteriotherapie des Typhus abdominalis. Wien. klin. 
Woch., 1915, xxviii, 64. 

McConkey, A. T. Bile salt media and their advantages in some bac- 
teriological examinations. Jour. Hyg., 1908, viii, 322. 



BIBLIOGRAPHICAL INDEX 271 

McCrae, T. C. Typhoid fever. Osier's System of Medicine, II, 1st Ed., 
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McWeeney, E. J. The agglutinability of different races of the typhoid 
bacillus. Lancet, 1899, i, 380. 

McWilliams, H. I. Treatment of typhoid fever with typhoid vaccine 
administered intravenously. Med. Rec, N. Y., 1915, lxxxviii, 648. 

Mehler, F. C. Prophylaxis of typhoid fever (typhoidin skin tests). 
Jour. Iowa State Med. Soc, 1916, March. 

Melnikowa, F. J. and Wersilowa, M. A. Zur Lehre von der Toxin- 
infektion. II. Ueber die Wirkung der Blutgifte zur die Agglutina- 
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Mertz. Uber Vaccinetherapie des Typhus abdominalis. Zt. f. Exper. 
Path, und Therapie, 1915, xvii, 224. 

Messerschmidt, Th. Bakteriologischer und histologischer Sektions- 
befund bei einer chronischen Typhusbazillentragerin. Zt. f. Hyg., 
1913, lxxv, 411. 

Metchnikoff, E. fitudes sur l'immunit^. Ann. Inst. Past., 1895, ix, 
433. 

(2) Etudes sur l'immunitd. Ann. Inst. Past., 1891, v, 465. 

Metchnikoff, E. and A. Besredka. Recherches sur la fievre typhoide 
experimentale. Ann. Inst. Past., 1911, xxv, 193. 

(2) Sur la vaccination contre la fievre typhoide. Compt. Rend. 
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(3) Des vaccinations antityphiques. Ann. Inst. Past., 1913, 
xxvii, 597. 

Meyer, F. Intravenose Typhusbehandlung mit sensibilisierten Bacillen- 
emulsion (Hochst). Berl. klin. Woch., 1915, Hi, 870. 

(2) Spezifische Typhusbehandlung. Berl. klin. Woch., 1915, lii, 
677. 

Meyer and Ahreiner. Ueber typhose Pyonephrose. Mitt. a.d. Grenz- 
gebieten der Med. und Chir., 1908, xix, H. 3. 

Meyer, F. and E. F. Altstaedt. Spezifische Typhusbehandlung. Berl. 
klin. Woch., 1915, No. 52, 677. 

Meyer, F. and Bergell. Ueber Typhusimmunisierung. Berl. klin. 
Woch., 1907, No. 18. 

Meyer, K. F. and C. R. Christiansen. The nature and specificity of the 
typhoidin reaction. Jour. Infec. Dis., 1917, xx, 391. 

Meyer, K. and E. Kilgore. The agglutinins and complement-fixing 
antibodies in serum of persons vaccinated against typhoid fever. 
Arch. Int. Med., 1917, Feb. 15. 



272 BIBLIOGRAPHICAL INDEX 

Milian. Lithiase biliare au cours de la fievre typho'ide. Gaz. hebd. de 
meU, 1896, 1137. 

Miller and Lusk. The use of foreign protein in the treatment of ar- 
thritis. Jour. Am. Med. Asso., 1916, lxvii, 2010. 

Minelli, S. Ueber Typhusbacillentrager und ihr Vorkommen unter 
gesunden Menschen. Cent. f. Bakt., xli, 1906, 406. 

Minet, J. Sur les complications des paratyphoides. Presse M&L, 1916, 
No. 4, 25. 

Montefusco. Sulla sieroterrapia antitifica. Jour. Int. d. Chir. Med., 
1908, xxx, 1. 

Moore, J. W. Text-book of the eruptive and continued fevers. Wm. 
Wood & Co., N. Y., 1892. 

Morgan, H. de R. Attempts to produce the typhoid carrier state in the 
rabbit. Jour. Hyg., 1911, 11, 202. 

Muller, P. T. Search for bacilli carriers. Munch, med. Woch., 1917, 
Jan. 2, lxiv, 1. (Rev. Jour. Am. Med. Asso., Mar. 24, 1917, 944.) 

Muller, R. and H. Graef. Nachweis von Typhusbakterien in ein 
gesandten Blutproben. Munch, med. Woch., 1906, Ixix, 411. 

Murchison, C. A treatise on the continued fevers of Great Britain. 
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(2) Contributions to the etiology of continued fevers. Med. Chir. 
Trans., March, 1858. 

(3) Account of a pig fed for six weeks on typhoid dejections. Trans. 

London Path. Soc, 1858, Nov., x. 

Naegeli, L. A. Blutkrankheiten und Blutdiagnostik. Veit. 2ed. Leip- 
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Naunyn, B. Klinik der Cholelithiase. Leipzig, 1892. 

Neisser, M. and R. Lubowski. Lasst sich durch Einspritzung von 
agglutinierten Typhusbazillen eine Agglutinproduktion hervorrufen. 
Cent. f. Bakt., 1901, xxx, 483. 

Neisser, M. and K. Shiga. Uber freie Rezeptoren von Typhus- und 
Dysenteriebazillen und iiber Dysenterietoxin. Deut. med. Woch., 
1913, Ixi. 

Netter, A. Observations. Bull, de TAcad. de M6d., 1911, lxvi, 351. 

Neufeld, F. and E. A. Lindemann. Beitrag zur Kenntnis der Serum- 
festen der Typhusstamen. Cent. f. Bakt., Ref. 1912, liv, Beihefte, 
229. 

Neuhaus. Nachweis der Typhusbazillen am Lebenden. Berl. klin. 
Woch., 1886, xxiii, 89. 



BIBLIOGRAPHICAL INDEX 273 

Nichols, H. J. Experimental observations on the pathogenesis of gall 
bladder infections in typhoid, cholera and dysentery. Jour. Exper. 
Med., 1916, xxiv, 497. 

(2) Observations on antityphoid vaccination. Jour. Exper. Med., 
1915, xxii, 780. 

Nicolle, C. and L. Blaizot. Les vaccins fluorur^s dans les vaccinations 
preventives et la vaccinotherapie. Arch. Inst. Past, de Tunis, 1914, 
ix, 1. 

Nicolle, C, A. Conor, E. Conseil. De Pinoculation intraveineuse des 
bacilles typhiques morts a Phomme. Compt. rend. Acad. Sciences, 
1912, civ, 1036. 

Nissle. Importing colon bacilli to fight pathogenic intestinal flora. 
Deut. med. Woch., 1916, xlii, 1181. (Jour. Am. Med. Asso., Dec. 2, 
1916, 1702.) 

Noak. Ueber Typhusimmunitat und Typhusimpfung. Zeit. f. klinik. 
Med., Berlin, 1915, lxxxii, 132. 

Noblecourt, P. and M. Petre. Complications observes au cours des 
fievres typhoiides et paratyphoides. Soc. M6d. des H6p., 1916, xxxii, 
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Nocard, E. and E. Leclainche. Les maladies microbiennes des animaux. 
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Nolp, P. De Taction antithermique et antiinfectieuse des injections 

intraveineuses de peptone. Compt. rend. Soc. Biol., 1916, lxxix, 649. 

(2) Parenteral injections of peptone in treatment of infectious 

diseases. Archives M6dicales Beiges, Paris, 1917, lxx, 97. 

(Jour. Am. Med. Asso., May 5, 1917, 1349.) 

Ogan. Immunization in a typhoid outbreak in the Sloane Hospital for 
Women. N. Y. Med. Jour., 1915, ci, 610. 

Ohno, K. Paratyphusbacillus ohne Gasbildungsvermogen. Cent. f. 
Bakt., 1915, lxxv, 288. 

Olmer. Fievres typhoides eberthiennes et paratyphiques de l'epid6mie 
de guerre. Revue de M6d., 1916, xxxv, 108. 

Ortiz, E., M. Acuna and L. Belloc. Bacteriothe>apie antityphique 
chez T enfant. Arch, de M6d. des Enfants, 1915, xviii, 573. 

Ostertag, R. Hanb. der Fleischbeschau. 1904. 

Park, W. H. Importance of ice in the production of typhoid fever. Jour. 
Am. Med. Asso., 1907, xlix, 852. 

(2) Typhoid bacilli carriers. Jour. Am. Med. Asso., 1908, li, 981. 

Park, W. H. and A. W. Williams. Pathogenic microorganisms. 4th ed. 
Lea and Febiger, N. Y., 1910. 



274 BIBLIOGRAPHICAL INDEX 

Patrick, A. Agglutination experiments with typhoid bacilli isolated 
from the body. Jour, of Hyg., 1914, xiv, 163. 

Paulicek, E. Zur Frage der Typhusheilimpfung. Wien. klin. Woch., 
1915, xxviii, 759. 

Peiper, E. Zur Frage der spezifischen Behandlung des Typhus abdom- 
inis. Deut. med. Woch., 1915, xli, 605. 

Penfold, W. J. Studies in bacterial variation. With special reference to 
the chemical functions of the members of the typhoid-coli group. 
Jour, of Hyg., 1911, xi, 30. 

Pensuti, V. Vaccination in typhoid. Policlinico, Rome, 1914, xx, 1805. 
(Jour. Am. Med. Asso.) 

Perussia, F. Sulla pretesa azione sterilizzante in vivo del cloroformio 
nell 'infezione tifosa. Pathologica, 1912, iv, 141. 

Pescarolo, B. and C. Quadrone. Aktive Immunisation durch sub- 
kutane Injektion lebender Typhusbazillen. Cent. f. inn. Med., 1908, 
xxix, 40. 

Petit and Serres. Traits de la fievre ent£ro-mdsenterique. Paris, 1813. 

Petrovh ch, M. Traitement de la fievre typhoide par l'hemoserotherapie 
daas l'armee serbe. Presse M6d., 1915, July 29. 

Petrtjschy. J. Ueber Massenauscheidung von Typhusbacillen durch den 
Urin von Typhusreconvalescenten und die epidemiologische Bedeu- 
tung dieser Thatsache. Cent. f. Bakt., 1898, xxiii, 577. 

(2) Spezifische Behandlung des Abdominaltyphus. Deut. med. 
Woch., 1902, xxviii, 212. 
Petzetakis. Vakzinotherapie antityphoidique intraveineuse. Comp. 
rend. Soc. Biol., 1916, lxxix, 655. 

Peutz, J. L. A. Vaccine therapy of typhoid. Bederl. Tijd. v. Geneesk., 
Amsterdam, 1916, ii, 555. (Quoted in Jour. Am. Med. Asso., 1916.) 

Pfaundler, M. Eine neue Form der Serumreaktion auf Coli- und Pro- 
teusbacillosen. Cent. f. Bakt., 1898, xxiii, 9, 71, 131. 

Pfeiffer, A. Ueber den Nachweis der Typhusbacillen im Darminhalt. 
und Stuhlgang. Deut. med. Woch., 1885, July 16, 500. 

Pfeiffer, R. Untersuchungen iiber das Choleragift. Zeit. f. Hyg., 1892, 

xi, 393. 
Pfeiffer, R. and G. Bessau. Zur Frage der Antiendotoxine bei Typhus 

abdominalis. Cent. f. Bakt., 1910, lvi, 344. 
Pfeiffer R. and W. Kolle. Experimentelle Untersuchungen zur 
Frage des Schutzimpfung des Menschen gegen Typhus abdominalis. 
Deut med. Woch., 1896, xxii, 735. 

(2) Ueber die specifische Immunitatsreaction der Typhusbacillen. 
Zt f. Hyg., 1896, xxi, 203. 



BIBLIOGRAPHICAL INDEX 275 

Piedvache. Recherches sur la contagion de la fievre typhoide. Mem. 
de 1 Acad, de Med., 1850, xv. 

Posselt, A. Atypische Typhusinfektion. Lubarsch-Ostertag, Ergebn. 
der allgem. Pathol., 19l2, xvi, 184. 

(2) Beziehungen zwischen Leber, Gallenwegen und Infektions- 
krankheiten. Lubarsch-Ostertag, Erbegn. d. allgem. Path., 
1915, xvii, 719. 

Pratt, J. H. Typhoid cholecystitis, with observations upon gallstone 
formation. Am. Jour. Med. Sci., 1901, Nov. 

Prigge. Studien iiber Typhusbazillentrager. Klin. Jahrb., 1909, xxii, 245. 

(2) Ortliche Ermittelungen iiber den Ursprung der Falle. (Bei wie 

vielen Fallen gelingt der Nachweis des Herkunfts? Umgebungs- 

untersuchen. Nachuntersuchungen Fragebogen.) Arb. a. d. 

kais. Ges., 1912, xli, 179. 

Prigge and Sachs-Muke. Beobachten bei zwei durch Nahrungsmittel 
verursachten Paratyphusepidemien. Klin. Jahrb., 1909, xxi, 225. 

Pringle. Diseases of the army. 4th ed. 1764. 

Prost. Medicine 6clair6e par l'observation et l'ouverture des corps. 
Paris, 1804. 

Pulay, E. Diagnostiche Hautreaktion bei Typhusrekonvaleszenten 
Typhuskranken, und Schutzgeimpften mit "Typhin" nach Gay und 
Force. Wien. klin. Woch., 1915, xxviii, 1189. 

Purjesz, B. Der Nachweis von Typhusbacillen im Duodenalinhalt bei 
Anwendung der Einhornschensonde. Hyg. Rundschau, 1915, xxv, 
601. 

Ramond, F. and G. Goubert. L'autohemoth^rapie appliqu^e au traite- 
ment de la fievre typhoide. Bull, de TAcad. de M6d., 1915, lxxiii, 208. 

Ranque and Senez. Action de l'iode sur le bacille d'Eberth. Compt. 
rend. Soc. Biol., 1913, lxxiv, 57. 

(2) L'immunite - sp^cifique et rimmunite* de groupe obtenues contre 
les bacilles typhiques et paratyphiques A et B par les vaccins 
iod6s. Bull. Acad, de MeU, 1915, lxxiv, 703. 

Reading, B. Isolation of B. typhosus from the bile in typhoid fever. 
Texas State Jour. Med., 1916, xii, 211. 

Reed, W., V. C. Vaughan and W. O. Shakespeare. Abstract of report 
on the origin and spread of typhoid fever in U. S. military camps 
during the Spanish War, 1898. Wash. Govt. Print. Office, 1900. 

Reibmayr, H. Uber Impstoffbehandlung des Typhus abdominalis auf 
intravenosen Wege. Munch, med. Woch., 1915, xlii, 610. 

Reiter. Uber thereapeutische Typhusvaccination. Deut. med. Woch., 
1915, No. 38, 1120. 



276 BIBLIOGRAPHICAL INDEX 

Remlinger, P. Ftevre typholde expe'rimentale par contamination 
alimentaire. Ann. Inst. Past., 1897, xi, 829. 

Remlinger, P. and Schneider. Presence du bacilles d'Eberth dans l'eau, 
le sol, et les matieres fecales, de sujets non atteints de fievre typholde. 
Compt. rend. Soc. Biol., 1896, ii, 105. 

Remond and Minvielle. Traitement de la fievre typholde par le se'rum 
de Rodet. Bull. Acad. Med., 1915, lxxiii, 321. 

Renaud, M. Resultats therapeutiques obtenus par 1'emploi du vaccin 
typhique irradie\ Presse M6d., Paris, 1911, xix, 665. 

(2) Vaccinotherapie par les vaccins irradies. Presse M6d., Paris, 
1911, xix, 585. 
Rhein, M. Zur Bakteriotherapie des Typhus abdominalis. Miinch. med. 

Woch., 1915, lxii, 427. 
Ribadeau, Dumas and Harvier. Recherches sur 1'elimination des 
bacilli d'Eberth et des paratyphiques par l'intestin. Compt. 
rend. Soc. Biol., 1910, lxix, 181. 

Richardson, M. W. A case of cholecystitis due to the typhoid bacillus. 
Bost. Med. & Surg. Jour., 1897, cxxxvii, 570. 

(2) On the role of bacteria in the formation of gall stones. Jour. 
Bost. Soc. Med. Sci., 1899, iii, 79. 

Richardson, M. W. and L. H. Spooner. Antityphoid inoculation as in- 
troduced into certain training schools for nurses in Massachusetts. 
Bost. Med. & Surg. Jour., 1911, clxiv, 8. 

Riecke. Der Kriegs- und Friedentyphus in den Armeen. Nordhausen, 

1850. 
Riedel. De febribus intestinalibus. Collect. Ballinger, 1776. 

Rimbaud, L. Diagnosis and prognosis of paratyphoid infection. Presse 
Med., 1916, vi, 305. (Jour. Am. Med. Asso., 1916, Nov. 19.) 

Rist, E. fitudes sur la fievre typholde. I. L'action de la vaccination 
antityphique sur la fievre typholde et les fievres paratyphoides. Ann. 
de Med., 1916, iii, 88. 

Robinson, H. Notes on the clinical characteristics of cases treated as 
paratyphoid fever. Lancet, 1915, ii, 851. 

Robinson, A. C. and L. F. Rettger. Studies in the use of brilliant green 
and a modified Endo's medium in the isolation of B. typhosus from 
feces. Jour. Med. Res., 1916, xxxiv, 363. 

Rocek, J. Ueber die Wirkung des Indols auf Typhusbazillenkulturen 
als Grundlage fur therapeutische Versuche. Cent. f. Bakt., 1915, 
lxxvii, 100. 

Rochoux. Le typhus nosocomial et la dothienenterite, sont ils la meme 
maladie? Arch. gen. de MeU, 1840, Feb. 



BIBLIOGRAPHICAL INDEX 277 

Rodet, A. Sur le propriety toxique de la culture de bacille d'Eberth et 
coli. Compt. rend. Soc. Biol., 1898, 1, 756. 

(2) S6roth<§rapie antityphoidique. Preparation du serum. Bull. 
Acad, de MeU, 1916, lxxvi, 85. 

(3) Se>oth6rapie antityphoidique. Bull. Acad, de MeU, 1916, 
lxxvi, 114. 

Rodet, A. and Lagriffoul. S6roth6rapie de la fievre typhoide; resultats 
cliniques. Compt. rend. Soc. Biol., 1910, lxviii, 605. 

Rodet, A., Lagriffoul and Wahby. La toxine soluble du bacille 
d'Eberth. Compt. rend. Soc. Biol., 1904, lvi, 794. 

Roederer and Wagler. De morbo mucoso. Gottingen, 1762. 

Roger, H. Principles of medical pathology. 2d Eng. ed. by Gabriel. 
Appleton & Co., 1905, N. Y. 

Rohonyi, H. Untersuchungen iiber das Wesen der therapeutischen 
Typhusvakzinwirkung. Zeit. f. klin. Med., 1916, lxxxiii, 60. 

Rommel and Herrmann. Klinische Beobachtungen aus der Schneide- 
miihler Typhusepidemie in Sommer 1911. Veroffentlichungen aus 
dem Gebiete der Medizinalverwaltung, 1912, i, 29. 

Roques, E. Contribution a l'6tude de la vaccinotherapie de la fievre 
typhoide par le virus-vaccin sensibilise" antityphique vivant de 
Besredka. Pub. Ch. Dirion, Toulouse, 1913. 

Rosenau, M. J. Preventive medicine and hygiene. Appleton & Co., 
1913, N. Y. 

Rosenau, M. J., L. L. Lumsden and J. H. Kastle. On the origin and 
prevalence of typhoid fever in the District of Columbia. Bull. No. 52, 
Hyg. Lab. U. S. Pub. H. & Mar.-Hosp. Sen'., 1909. 

Roth, N. Versuche iiber die Einwirkung des Caffeins auf das Bacterium 
Typhi und coli. Hyg. Rundschau, 1903, No. 10. 

Rothberger, C. J. Differentialdiagnostische Untersuchungen mit 
gefarbten Nahrboden. Cent. f. Bakt., 1898, xxiv, 513. 

Roux, E. and Chamberlain. Immunity contre le septicernie confere" par 
des substances solubles. Ann. Inst. Past., 1887, i, 561. 

Rovsing, Th. Klinische und experimentelle Untersuchungen iiber die 
infektiosen Krankheiten der Harnorgane. A. d. Danischen, Berlin, 
1898. 

Ruediger, G. F. and R. Hulbert. Is dried blood as reliable as fresh 
serum in making the Widal test? Am. Jour. Pub. Health, 1914, iv, 
113. 

Ruhr'ah, John. Infectious diseases, including acute rheumatism, 
croupous pneumonia and influenza. Prog. Med., 1916, March, 133. 



278 BIBLIOGRAPHICAL INDEX 

Rumpf, T. Die Behandlung des Typhus abdominalis mit abgetodteten 
Culturen des Bacillus Fyocyaneus. Deut. med. Woch., 1893, xix, 987. 

Russell, F. F. Progress in antityphoid vaccination during 1912. Jour. 
Am. Med. Asso., 1913, lxi, 665. 

(2) The isolation of typhoid bacilli from urine and feces with the 
description of a new double sugar tube medium. Jour. Med. 
Res., 1911-12, xxv, 217. 

Sachs, H. Die Schutzimpfung gegen Typhus. Med. Klinik, 1914, 1538. 

Sacque>ee, E. Les porteurs de germes. Bull. Inst. Past., 1910, viii, 
1, 49. 

Sacque>ee, E., Burnet and Weissenbach. Etude macroscopique des 
lesions produites chez l'homme par le bacille paratyphique A, d'apres 
le protocole de 9 autopsies. Presse M6d., 1915, Sept. 8. 

Sacquepee, E. and F. Chevrel. Les bacilles paratyphiques. Bull. 
Inst. Past., 1907, v, 49. 

(2) Sur la vaccinotherapie antityphoi'dique. Soc. m£d. des H6p. de 
Paris, 1913, 845. 

Sadler. The antigen treatment of enteric fever. Quart. Jour, of Med., 
1912, v, 193. 

Salmon, E. and T. Smith. On a new method of producing immunity 
from contagious diseases. Proc. Biol. Soc. of Washington, 1884-6, 
iii, 29. 

(2) The bacterium of swine plague. Am. Monthly Microscopical 
Jour., 1886, Nov., 204. 

Sanarelli, J. Etudes sur la fievre typhoide exp^rimentale. Ann. Inst. 
Fast., 1894, viii, 193. 

(2) Etiologie et pathogenie de la fievre jaune. Ann. Inst. Past., 
1897, xi, 433. 

Sarrailhe, A. and J. Clunet. La "jaunisse des camps" et l'6pidemie 
de paratypho'fde des Dardenalles. Bull, et Mem. Soc. MeYl. des Hop., 
I aris, 1916, xl, 45. 

Sartory, A., L. Spillmann and P. Lasseur. Etats typhoides pendant 
la campagne 1914-15. Bull. Acad. MeU, 1915, Ixxiii, 385. 

Sawyer, W. A. Ninety-three persons infected by typhoid carrier at pub- 
lic dinner. Jour. Am. Med. Asso., 1914, lxiii, 1537. 

(2) A typhoid carrier on shipboard. Jour. Am. Med. Asso., 1912, 

Iviii, 1336. 

(3) The disease carrier on train and steamboat. Jour, of Sociologic 

Medicine, 1916, xvii. 

(4) The efficiency of various antityphoid vaccines. Jour. Am. 

Med. Asso., 1915, lxv, 1413. 



BIBLIOGRAPHICAL INDEX 279 

Scheller, R. Beitrage zur Typhusepidemiologie. Cent. f. Bakt., 1908, 
xlvi, 385. 

Schlager. Kriegesarzte Abend der V. armee am 14 Dez., 1914. Munch, 
med. Woch., 1914, Dec. 14. 

Schmitz, K. E. F. Die Brauchbarkeit des Kongorotnahrbodens zur 
bakteriologischen Typhusdiagnose. Deut. med. Woch., 1915, xli, 425. 
(2) Ein neuer Elektionahrboden fur Typhusbacillen. Cent. f. 
Bakt., 1915, lxxvi, 306. 

Schneider, F. Ueber Leukopenic und Aneosinophilie nach Typhus- 
schutzimpfung. Deut. med. Woch., 1915, xli, 426. 

Schoenlein. Allgemeine und specielle Pathologie und Therapie. Frey- 
burg, 1839. 

Scholz. Bemerkungen zur Symptomatologie und Therapie des Unter- 
leibstyphus. Deut. med. Woch., 1915, xli, 1456. 

Schottmuller, H. Die typhosen Erkrankungen. Handb. der inn. Med., 
i, 397. 

(2) Weitere Mitteilungen iiber mehrere das Bild des Typhus 
bietende Krankheitsfalle, hervorgerufen durch typhusahnliche 
Bacillen. Zt. f. Hyg., 1900, xxxvi, 368. 

Schtulern, W. R. De la bacteriemie typhique et ses rapports avec le 
pouvoir agglutinant du seVum au cours de la fievre typhoi'de. Roussky 
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Schuder. Zur Aetiologie des Typhus. Zeit. f. Hyg., 1901, xxxviii, 343. 

Schumacher. Zur Frage der Bazillentrager und ihrer Beziehung zum 
endemischen Typhus. Klin. Jahrb., 1909, xxii, 263. 

Schurmann. Zur Beschleunigung und Vereinfachung der Typhus- 
bazillenzuchtung aus dem Blut. Deut. med. Woch., 1916, xlii, 158. 

Scott, H. H. An investigation into the causes of the prevalence of enteric 
fever in Kingston, Jamaica; with special reference to the question of 
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Scully, F. J. The reaction after intravenous injections of foreign protein. 
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Sedgwick, W. T. Introduction to Whipple's Typhoid Fever, 1908. 
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Sedgwick, W. T. and S. MacNutt. An examination of the theorem of 
Allen Hazen, that for every death from typhoid fever avoided by the 
purification of public water supplies, two or three deaths are avoided 
from other causes. Science, 1908, p. 215, N. S. 28. 

Seiffert, S. Ueber Mitagglutination de Gaertnerbazillen, ein Hilfs- 
mittel zur Typhusdiagnose. Miinch. med. Woch., 1915, Ixii, 1753. 



280 BIBLIOGRAPHICAL INDEX 

Seitz, C. Der Abdominaltyphus nach langjahriger Beobachtung. Stutt- 
gart, Enke, 1888. 

Semple, D. and E. D. W. Greig. An enquiry on enteric fever in India. 
Scientific memoir by officers of the medical and sanitary department 
of the Government of India. No. 32, Calcutta, 1908. 

Sergent, E. and L. Negre. Les vaccinations mixtes antityphoidiques et 
antiparatyphoidiques dans l'arm^e de l'Afrique du Nord. Bull. Acad. 
MeU, 1915, Oct. 26, 469. 

Shaffer, P. A. and W. Coleman. Protein metabolism in typhoid fever. 
Arch. Int. Med., 1909, iv, 538. 

Shattuck. Observations of typhus and typhoid fever. Am. Med. 
Examiner, Feb. and Mar., 1840. 

Shimidsu, K. Ueber die Morphologie des Bact. coli, B. typhi abdominalis 
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338. 

Sick, K. Ueber die klinische Verwendung von Blutnahrboden, ihren 
Einfluss auf Immunitatsreaktionen und uber das Verhalten der 
Bakterien (speziell der Tuberkelbacillen) zum Hamoglobin. Cent, 
f. Bakt., 1912, lxiv, 111. 

Simon, G. Ueber Cholecystitis typhosa als Ursache chronischer Typhus- 
bazillenausscheidung. Klin. Jahresbericht, 1907, xvii, 363. 

Sinnhuber. Die Bekampfung der Kriegesseuchen durch Schutzimpfung. 
Deut. med. Woch., 1915, xli, 637. 

Sirotinin, W. Die Uebertragung von Typhusbacillen auf Versuchs- 
thiere. Zt. f. Hyg., 1886, i, 465. 

Sladek, J. and S. Kotlowski. Zur Vakzinetherapie des Typhus ab- 
dominalis. Wien. klin. Woch., 1915, xxviii, 389. 

Smith, F. Antityphoid or anti-enteric inoculation. Jour. Trop. Med., 
1904, vii, 271. 

Smith, H. The typhoid bacillus and typhoid fever. Brit. Med. Jour., 
1900, i, 827. 

Smith, J. H. The identification of the pathogenic members of the 
typhoid-colon group of bacilli. Brit. Med. Jour., July 3, 1915. 

Smith, Nathan. Medical and Surgical Memoirs, 1824, p. 47. 

Smith, T. Active immunity produced by so-called balanced or neutral 
mixtures of diphtheria toxin and antitoxin. Jour. Exp. Med., 1909, 
xi, 241. 

Southard, E. E. and E. T. F. Richards. Typhoid meningitis: cultiva- 
tion of Bacillus typhosus from meninges and mesenteric lymph node, 
etc. Jour. Med. Res., 1908, xix, 513. 



BIBLIOGRAPHICAL INDEX 281 

Spigelius. De febre semi terti ana. Frankfurt, 1624. 

Spitta. Die Washer versorgung. Handb. d. Hyg., 11, 39. Rubner, 
Griiber, Ficker, 1913, Hirzel, Leipzig. 

Spooner, L. H. Antityphoid inoculation. Jour. Am. Med. Asso., 1912, 
lix, 1359. 

Stenitzer, R. Ueber die Toxine (Endotoxine) der Typhusbazillen, 
Kraus and Levaditi Handb. d. Immunitatsforsch., 1908, i, 193. 

Stepp. Die Duodenalsonde zum Nachweis der Typhusbazillen in der 
Galle von Typhusrekonvaleszenten. Miinch. med. Woch., 1915. 
lxii, 1676. 

Stern, R. Ueber die Wirkung des menschlichen Blutserums auf die 
experimentelle Typhusinfektion. Zt. f. Hyg., 1894, xvi, 458. 

Stern, R. and W. Korte. Ueber den Nachweis der bakteriziden Reak- 
tion im Blutserum der Typhuskranken. Berl. klin. Woch., 1904. 

Sterzing, P. Ueber Recidive und Nachschiibe beim Typhus abdom- 
inal is. Diss., Leipzig. 

Stokes, A. and C. Clarke. Search for typhoid carriers. Lancet, 1916, 
566, 590. 

Stoner, H. W. Antibody production by typhoid vaccines. Jour, of 
Immunol., 1916, i, 511. 

Strong, R. P. Some questions relating to the virulence of microorganisms 
with particular reference to their immunizing powers. Jour. Exper. 
Med., 1905, vii, 229. 

Strother. A very remarkable history of a spotted fever. London, 1729. 

Stursburg and Klose. Zur Frage der Bewertung der franzosischen 
Typhusschutzimpfung der Griiber-Widalschen Reaktion bei Typhus- 
geimpften. Miinch. med. Woch., 1915, lxii, 380. 

Sutton, J. B. On the diseases of monkeys in the Society's Gardens. 
Zool. Soc. Proc, 1883, 581. 

Szecsy, E. Die Behandlung des Typhus abdominalis mit Besredkas 
Vakzine. Deut. med. Woch., 1915, xli, 966. 

Tanaka, K. Bacteriological investigation of typhoid fever. Korea Med. 
Soc, 1914, No. 12, 22. (China Med. Jour., 1917.) 

Tarassevitch, L. Vaccinations antityphiques dans l'armee russe. Bull. 
Acad, de MeU, 1916, May 9. 

Taylor. On the communication of fever by ingestion. Ed. Med. Jour., 
1858, June. 



282 BIBLIOGRAPHICAL INDEX 

Teagde, 0. and H. I. McWilliams. The bacteriolytic power of normal 
and immune rabbit serum for typhoid bacilli and the influence of the 
intravenous injection of vaccine upon the same. Jour, of Immunol., 
1917, ii, 167. 

(2) Experiments with a possible bearing upon treatment of typhoid 
fever with typhoid vaccine administered intravenously. Jour, 
of Immunol., 1917, ii, 185. 

(3) The bacteriolytic power of normal human sera and typhoid 
patients' sera for typhoid bacilli and an inquiry into the 
theoretical basis for the treatment of typhoid fever with vac- 
cine administered intravenously. Jour, of Immunol., 1917, ii, 
193. 

Terrile, A. (Quoted by Posselt). Atypische Typhusinfektion. Lu- 
barch-Ostertag Ergebn., 1912, xvi, 184. 

Thayer, W. S. Two cases of post typhoid anemia with remarks on the 

value of examination of the blood in typhoid fever. Johns Hopkins 

Hosp. Reports, 1895, 83. 
Thiroloix, J. and Bardon. Vaccin typhique intraveineux. Soc. M6d. 

des Hop., 1913, xxxvi, 108. 
Tidy, H. L. Influence of febrile conditions on inoculation agglutinins. 

Lancet, 1916, i, 241. 

Tolmer and Weissenbach. Un cas de meningite ce>£bro-spinale aigue 
primitive a bacille paratyphique A. Presse M£d., 1915, Sept. 9, 
No. 42. 

Tonnel. fitudes des reactions humorales dans la vaccination anti- 
typhoidique et antiparatyphoidique A et B. Lyon Med., April, 1916, 
cxxv. 

Tonney, F. 0., F. C. Caldwell and P. J. Griffin. The examination of 
the urine and feces of suspect typhoid carriers with a report on 
elaterin catharsis. Jour. Inf. Dis., 1916, xviii, 239. 

Torrey, J. C. The fecal flora of typhoid fever and its reaction to various 
diets. Jour. Inf. Dis., 1915, xvi, 72. 

Townsend, J. H. Antityphoid vaccination. Am. Jour. Pub. Health, 
1914, iv, 993. 

Tremolieres, F., P. Loew and Matllart. Recherches sur la vaccina- 
tion antitypholdique par la voie digestive. Bull. Acad. M6d., 1915, 
Oct. 26, p. 477. i 

Trowbridge, E. H., B. A. Finkle and E. M. Barnard. Report of a 
typhoid epidemic occurring three months after the use of prophylactic 
vaccine. Jour. Am. Med. Asso., 1915, lxiv, 728. 

Tsuzuki, J. Fine von Bazillentragern hervoreerufcne Tvphusenidemie 
in der XV Division von Japan. Arch. f. Schiffs- und Tropenhygiene, 
1910, xiv, 147. 



BIBLIOGRAPHICAL INDEX 283 

Tsuzuki, M. and K. Ishida. Ueber die Beeinflussung der Typhusbazillen 
bei Typhusrekonvaleszenten durch Kalium jodatum sowie Acidum 
arsenicosum. Deut. med. Woch., 1910, Sept. 1, 1005. 

Tubby, A. H. and J. A. B. Hicks. A case of suppurative post-typhoid 
osteitis thirteen years after an attack of enteric fever. Lancet, 1913, 
i, 304. 

Twort, F. W. The fermentation of glucosides by bacteria of the typhoid 
coli group and the acquisition of new fermenting by Bacillus dys- 
enteriae and other microorganisms. Proc. Roy. Soc, London, 1907, 
lxxix, 329. 

Uhlenhuth, P. and E. Hubener. Infektiose Darmbakterien der Para- 
typhus und Gaertner-gruppe einschliesslich Immunitat. Kolle & 
Wassermann Handbuch der pathogen. Mikroorganismen. 1913, Hi, 
1005, Fischer, Jena. 

Uhlenhuth, P. and T. Messerschmidt. Versuche Kaninchen zu 
Typhusbazillentragern zu machen und sie therapeutisch zu beein- 
flussen. Deut. med. Woch., 1912, xxxviii, 2397. 

Uhlenhuth, P., Olbrich and T. Messerschmidt. Typhusverbreitung 
und Typhusbekampfung im Felde. Med. Klinik, 1915, No. 6, 149. 

Valleix. Considerations sur la fievre typhoide. Arch. g6n. de M6d., 

1839, Jan., Feb., Oct., and Nov. 
Vaughan, V. C. The specific treatment of typhoid fever. Am. Jour. 

Med. Sci., 1908, Sept. 

(2) Protein split products in relation to immunity and disease. 
Lea and Febiger, 1913. 
Venema, T. A. Ueber Agglutination von Bakterien der Typhusgruppe 

durch Galle. Berl. klin. Woch., 1906, No. 30. 
Vilchur. Etiology and clinical bacteriology of typhoid fever. Inaug. 

Diss., St. Petersburg, 1887. 
Vincent, H. See Vincent and Muratet. 

(2) Sur la vaccination antityphique. Jour. State Med., 1912, xx, 
322. 

(3) Sur l'immunisation active de l'homme contre la fievre typhoide. 
Compt. rend. Acad, des Sci., civ, 480. 

(4) Remarques sur la vaccination antityphique. Ann. Inst. Past., 

1911, xxv, 455. 

(5) Sur la vaccination antityphique. Jour. State Med., 1912, xx, 
321. 

(6) Nouvelles remarques sur le vaccin mixte antityphoidique et 
antiparatyphique. Presse M<5d., Sept. 2, 1915. 

(7) Action du vaccin antityphoTdique chez los sujets en incubation 
de la fievre typhoide ou infcctfe au cours de l'immunisation. 
Compt. rend." Acad. Sci., 1913, clvi, 821. 



284 BIBLIOGRAPHICAL INDEX 

(8) Un nouveau cas de la contagion eberthienne de laboratoire 

pr^venu par le vaccination antityphoidique (vaccin polyva- 
lent). Compt. rend. Soc. Biol., 1914, lxxvi, 32. 

(9) Reference by Vincent and Muratet, 1. c. 162. 

(10) Re'sultats de la vaccination antityphoidique par le vaccin 
polyvalent. Bull, de l'Acad. de M6d., lxxvii, No. 19, 475. 

Vincent, H. and L. Muratet. Fievres typholdes et paratyphoides. 
Masson & Co., Paris, 1916. 

von Behring, E. Ueber ein neueres Diphtherieschutzmittel. Deut. med. 
Woch., 1913, xxxix, 873. 

von Jaksch, R. Ueber die Behandlung des Typhus abdominalis mit 
Blutserum von Typhusrekonvaleszenten. Verhand. d. Kong. f. inn. 
Med., Wiesbaden, 1895. 

Wade, E. M. and 0. McDaniel. Observations on the Widal reaction 
following the administration of typhoid vaccine. Am. Jour. Pub. 
Health, 1915, v, 136. 

Waitzfelder, E. Treatment of typhoid with bacterins. N. Y. Med. 
Jour., 1916, ciii, Feb. 26. 

Walger, E. Beitrag zur Behandlung des Abdominaltyphus mit mensch- 
lichem Rekonvalescentenblutserum. Cent. f. inner. Med., 1898, 941. 

Ward, W. A. Some notes on the results of anti-enteric inoculation. 
Jour. Roy. Army Med. Corps, 1906, vi, 436. 

Wassermann, A. Uber Agglutinine und Pracipitine. Zt. f. Hyg., 1903, 
xlii, 267. 

(2) Beitrage zur Typhus-Schutzimpfung. Zt. f. Hyg., 1911, lxx, 
204. 

(3) Zur aktiven Immunisierung des Menschen. Festschr. z. 60. 
Geburtst. von R. Koch, p. 527. Fischer, Jena, 1904. 

Weichardt, W. tlber die unspezifische Therapie von Infektionskrank- 
heit. Munch, med. Woch., 1915, lxii, 1525. 

Weil, P. E. Vaccinotherapie de la fievre typhoide chez l'enfant. Soc. 
m6d. des hop. de Paris, 1913, xxxvi, 344. 

Weinfurter, F. Experimentalle Typhusbazillentrager bei Kaninchen. 
Cent. f. allg. Pathol., 1915, xxvi, 367. 

Weiss, H. Cultural and antigenic differences in strains of Bacillus 
typhosus and studies in the paratyphoid group. Jour. Med. Res., 
1917, xxxvi, 135. 

Werner, A. Sur la toxine secreted par le bacille typhique. Compt. rend. 
Soc. Biol., 1904, lvi, 882. 

Whipple, G. C. Typhoid fever: its causation, transmission and preven- 
tion. Wiley & Sons, 1908. 



BIBLIOGRAPHICAL INDEX 285 

Whittington, T. H. The use of stock vaccine in infection by the Bacil- 
lus typhosus with an analysis of 230 cases. Lancet, 1916, No. 4832, 
759. 

Widal, F. Serodiagnostic de la fievre typhoide. Bull, et mem. Soc. m£d. 
d. hop. ,1896, vi, 26. 

(2) Reference in Brouardel and Thoinot, 1. c. 29. 

(3) A propos de la vaccination antityphoidique. Bull. Acad, de 
MeU, 1915, lxxiii, 363. 

(4) Sur les vaccinations mixtes antityphoidiques et antiparaty- 
pholdiques. Bull. Acad. M6d., 1915, lxxiv, 249. 

(5) Etude sur les vaccinations mixtes antityphoidiques et antipara- 
typholdiques. Presse Med., 1915, No. 38, 305. 

(6) fitudes sur les vaccinations mixtes antityphoidiques et anti- 
paratyphoidiques. Bull. Acad. M6d., Aug. 10, 1915, 149. 

(7) R6sultats de la vaccination antityphique. Presse M6d., 1915, 
No. 53, 437. 

Widal, F. and Courmont. Revaccination antityphoidique et vaccina- 
tion antiparatyphoidique. Presse M6d., 1916, No. 8, 57. 

Widal, F. and L. LaSourd. Recherches exp^rimentales et cliniques sur 
la s^nsibilitrice dans le serum des typhiques. Compt. rend. Soc. 
Biol., 1901, liii, 841. 

Widal, F. and A. T. Salimbeni. Reduction du nombre des injections 
employees pour la vaccination mixte antityphoidique et antipara- 
typhoidique A et B. Presse M6dicale, 1917, xxv, 1. 

Widal, F. and A. Sicard. Etude sur le serodiagnostic et sur la reaction 
agglutinante chez les typhiques. Ann. Inst. Past., 1897, xi, 353. 

Willis. De febribus. 1659. 

(2) Opera omnia Amstelodami. 1682. De morbis convulsivis, 
Cap. 8. 

Wilman. Detection of typhoid bacilli in search for carriers. Norsk. 
Magazin for Laegevidenskaben, 1916, lxxvii, 879. (Jour. Am. Med. 
Asso., 1916). 

Wilson, W. J. and C. Dickson. A rapid gravimetric method of stand- 
ardizing vaccines. Jour, of Hyg., 1912, xii, 49. 

Wiltshire, H. W. and A. MacGillycuddy. Treatment of typhoid by 

stock typhoid vaccine. Lancet, 1915, ii, 685. 
Winslow, A. E. Technology Quarterly, 1901, xiv. 

Wolff-Eisner, A. Die Ophthalmo- und Kutandiagnose der Tuber- 

kulose. Wurzburg, 1908. 
Wolfsohn, G. Appendicitis und Typhus. Berl. klin. Woch., 1915, xli, 

872. 



286 BIBLIOGRAPHICAL INDEX 

Woodruff, C. E. Tuberculosis following typhoid fever.J'Am. Med., 
1914, N. S. 9, 17. 

Wright, A. E. On the association of serous hemorrhages with conditions 
of defective blood coagulability. Lancet, 1906, ii, 802. 

(2) Zur Geschichte der Typhusschutzimpfung des Menschen. 
Cent. f. Bakt., 1908, xlvi, 188. 

(3) On the protective value of antityphoid inoculation. Lancet, 
Sept. 6, 1902, 651. 

Wright, A. E. and Semplb. Remarks on vaccination against typhoid 
fever. Brit. Med. Jour., Jan. 30, 1897, 256. 

Yagisawa, M. La vaccination antityphique dans l'armSe japonaise. 
Paris Med., 1916, vi, 490. 

Yamanouchi, T. Toxicity du filtrat des cultures en bouillen des bacilles 
typhiques et paratyphiques. Compt. rend. Soc. Biol., 1909, lxvi, 
1050. 

Ziersch, P. Beobachtungen bei Typhusschutzgeimpften. Munch, med. 
Woch., 1915, Ixii, 1310. 

Zinsser, H. Infection and resistance. Macmillan Co., N. Y., 1914. 

Zupnic, L., A. von Muller and K. Leiner. Erfahrungen uber Praxis 
und Theorie der Vakzinetherapie. Wien. klin. Woch., 1916, xxix, 33. 



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